Immunity & Ageing, 2007; 4: 1-1 (más artículos en esta revista)

La interleucina-6 inflamación de la vía con el envejecimiento de colesterol - Papel de las estatinas, los bifosfonatos y la planta de polifenoles en el envejecimiento y la edad de las enfermedades relacionadas con

BioMed Central
Sota Omoigui (Medicinechief@aol.com) [1]
[1] División de la inflamación y el dolor de Medicina, Luisiana Pain Clinic, 4019 W. Rosecrans Ave, Los Angeles, CA 90250, EE.UU.

Este es un artículo de acceso abierto distribuido bajo los términos de la licencia Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0], que permite el uso ilimitado, distribución y reproducción en cualquier medio, siempre que la obra original es debidamente citados.

Resumen

Se describe la inflamación de la vía del colesterol con el envejecimiento. Interleucina 6 mediada por la inflamación está implicada en edad-incluidos los trastornos relacionados con la aterosclerosis, enfermedad vascular periférica, enfermedad de las arterias coronarias, osteoporosis, diabetes tipo 2, demencia y la enfermedad de Alzheimer y algunas formas de artritis y el cáncer. Las estatinas y los bisfosfonatos inhiben la interleucina 6 inflamación mediada indirectamente a través de la regulación de la síntesis endógena de colesterol y isoprenoid agotamiento. Compuestos polifenólicos encontrados en plantas, frutas y hortalizas interleucina 6 inhibir la inflamación mediada por la inhibición directa de la vía de transducción de señales. Dianas terapéuticas para el control de todas estas enfermedades deben incluir la inhibición de la interleucina-6 mediada por la inflamación.

Fondo

En 400 aC, Hipócrates reconoció la relación entre la salud y la alimentación. Él dijo: "Que la alimentación sea tu medicina y la medicina sea tu alimento". En 1513, el explorador español Juan Ponce de León descubrió Florida mientras que la búsqueda de la Fuente de la Juventud, un mítico primavera dijo a restaurar la juventud. Ponce de León murió tratando de encontrar esas aguas. Tendría que haber estado buscando lugar para la Flora de la Juventud y los inhibidores de la interleucina 6 mediada por la inflamación.

El envejecimiento se asocia con una mayor frecuencia de trastornos entre ellos varios aterosclerosis, enfermedad vascular periférica, enfermedad de las arterias coronarias, osteoporosis, diabetes tipo 2, demencia y la enfermedad de Alzheimer y algunas formas de artritis y el cáncer. El envejecimiento se caracteriza también por un estado proinflamatorio que contribuye a la aparición de la discapacidad y de edad las enfermedades relacionadas con el. Citoquinas proinflamatorias desempeñan un papel central en la mediación celular y las respuestas fisiológicas. Los estudios de los efectos del envejecimiento sobre la respuesta inflamatoria mostrar interleukina-6 (IL-6), factor de necrosis tumoral alfa (TNF-alfa) y la interleucina-1beta (IL-1beta) a ser importante [1]. Esta revisión se centrará en la inhibición de la interleucina 6 inflamación mediada como clave para la prevención y el tratamiento del envejecimiento y la relacionada con la edad trastornos.

La aterosclerosis

Las enfermedades cardiovasculares (ECV) es la principal causa de muerte y discapacidad en los países desarrollados y está aumentando rápidamente en el mundo en desarrollo. Para el año 2020, se estima que las enfermedades cardiovasculares se superan las enfermedades infecciosas como el mundo la primera causa de muerte y discapacidad. Enfermedad vascular aterosclerótica (ASVD), que abarca la cardiopatía coronaria, enfermedad cerebrovascular y enfermedad arterial periférica, es responsable de la mayoría de los casos de las enfermedades cardiovasculares en países en desarrollo y desarrollados [2]. La aterosclerosis, una enfermedad progresiva caracterizada por la acumulación de lípidos y elementos fibrosos en las arterias, constituye la más importante contribuyente a esta creciente carga de enfermedades cardiovasculares. El vínculo entre el metabolismo de los lípidos y la aterosclerosis dominado el pensamiento hasta la década de 1980 [3]. En los últimos quince años, sin embargo, un papel destacado para la inflamación en la patogénesis de la aterosclerosis se ha establecido [4]. Ahora, la aterosclerosis es considerada como una inflamación mediada por la enfermedad impulsada por complejas interacciones entre leucocitos, plaquetas y células de la pared vascular.

Lesión endotelial es el primer y crucial paso en la patogénesis de la aterosclerosis. Una plétora de determinadas genéticamente y factores epigenéticos, como oxidados las lipoproteínas de baja densidad (LDL), los radicales libres (por ejemplo, debido al consumo de cigarrillos), la hipertensión, la diabetes mellitus, elevación de homocisteína plasmática, los microorganismos infecciosos, reacciones autoinmunes, y combinaciones de las mismas, Se han identificado como etiológico principios. Lesión endotelial provoca la inflamación con un aumento de la adhesividad y la activación de leucocitos (principalmente monocitos) y plaquetas, que es acompañada por la producción de citocinas, quimiocinas, moléculas vasoactivas y factores de crecimiento.

La característica distintiva de la lesión aterosclerótica temprana es el colesterol éster-carga (CE-carga) de espuma de células macrófagos [5]. Progresista "libre" de colesterol (FC) de carga lesional de macrófagos lleva a una serie de fosfolípido relacionados con las respuestas de adaptación. Estas respuestas de adaptación eventualmente fracasan, lo que los macrófagos de muerte. Macrófagos muerte por necrosis lesional conduce a la necrosis, la liberación de las proteasas celulares, citoquinas inflamatorias, y protrombóticos moléculas, que podrían contribuir a la inestabilidad de la placa, la ruptura de la placa, trombóticos agudos y oclusión vascular [6]. En efecto, áreas necróticas de lesiones ateroscleróticas avanzadas son las que se sabe están asociados con la muerte de los macrófagos, y la ruptura de placas de lesiones humanos han demostrado ser enriquecido en los macrófagos apoptóticos. La presencia de apoptosis y necrosis macrófagos en lesiones ateroscleróticas ha sido bien documentado en muchos humana y animal, estudios [7, 8].

Actualmente, los mediadores inflamatorios implicados en la patogénesis de la aterosclerosis incluyen citocinas, quimiocinas, moléculas vasoactivas y factores de crecimiento. Los efectos antiinflamatorios de las estatinas se atribuyen a polifacético mecanismos, entre ellos la inhibición de la progresión del ciclo celular, la inducción de la apoptosis, la reducción de la ciclooxigenasa-2 y una actividad bifásico, dependiente de la dosis efecto sobre la angiogénesis [9]. En el centro de estos mecanismos está la capacidad de inhibir la proteína G prenylation a través de una reducción de farnesylation y geranylgeranylation [10].

Con el fin de avanzar en el actual teorías y el pensamiento [11], y aclarar la relación entre estas enfermedades comunes, presentar nuestra teoría de la vía bioquímica precisa, entre el colesterol y la inflamación, y entre la inflamación y el envejecimiento y la edad-incluidos los trastornos relacionados con la aterosclerosis, Enfermedad vascular periférica, enfermedad de las arterias coronarias, osteoporosis, diabetes tipo 2, demencia y la enfermedad de Alzheimer y algunas formas de artritis y el cáncer. En la elaboración de esta vía bioquímica, vamos a delinear un mecanismo de los efectos pleiotrópicos de las estatinas, drogas y bifosfonato compuestos polifenólicos. El mecanismo común de acción comunes y efectos pleiotrópicos de las estatinas, drogas y bifosfonato planta de derivados sintéticos y compuestos polifenólicos, además de nuestra determinación de la única actividad de la citoquina interleucina 6 entre todos la gran mediadores de la inflamación y la respuesta inflamatoria, nos ha permitido utilizar técnicas de ingeniería inversa esta vía bioquímica. Cada componente de nuestra teoría está respaldada y validada por numerosos estudios de investigación.

Respuesta de fase aguda

La respuesta de fase aguda se produce antes de anticuerpos mediada por la defensa inmunológica. Se produce en respuesta a una respuesta inflamatoria provocada por las lesiones y traumas, neoplasias, trastornos inmunológicos o actividad. Una reacción local en el sitio de lesión o infección conduce a una activación de citoquinas (concretamente, IL-6, IL-1, TNF-alfa, y los interferones) que desencadena una respuesta sistémica que consta de leucocitosis, aumento de la producción de glucocorticoides; aumentos en las tasas de velocidad de sedimentación, fiebre, activación del complemento y la cascada de coagulación; disminuye a niveles séricos de zinc y hierro, y un aumento en los niveles plasmáticos de proteínas de fase aguda, proteína C reactiva (PCR), amiloide A sérico, fibrinógeno y otras proteínas [12 ].

Los niveles de citoquinas que participan en la respuesta de fase aguda - TNF-alfa, IL-1, IL-6, fibrinógeno y - han demostrado ser elevados en los casos de angina inestable en relación con aneurisma [13 - 15] y se han correlacionado positivamente con el riesgo de primaria y el infarto de miocardio recurrente y la muerte [16 - 18]. El riesgo asociado a estos niveles elevados se mantiene constante, incluso cuando los datos se ajusta para otros los principales factores de riesgo: tensión arterial, colesterol y HDL, índice de masa corporal, la diabetes, uso de alcohol, antecedentes familiares, y en el ejercicio de frecuencia [15]. Niveles elevados de altamente sensible proteína C-reactiva (hs-CRP) se han relacionado con mayor riesgo de enfermedad cardiovascular, infarto de miocardio y enfermedad arterial coronaria (CAD) de muertes entre las personas con angina de pecho [19 - 21]. Ensayaron los niveles de hs-CRP puede aumentar más de 100 veces los niveles normales dentro de 24-48 horas después de un estímulo inflamatorio agudo. Sin embargo, a largo plazo entre los estudios prospectivos de las variaciones individuales en hs-Los niveles de PCR pueden ocurrir durante largos períodos de tiempo, en ausencia de trauma o infección aguda [22] niveles elevados de hs-CRP han puesto de manifiesto una duplicación del riesgo tanto para isquémica accidente cerebrovascular en pacientes hipertensos hombres y mujeres [14, 23] y para la enfermedad arterial periférica [24].

Estudios recientes están demostrando que la IL-6 y TNF-alfa son más fuertes predictores de la enfermedad cardiovascular de proteína C reactiva. En la Salud, el Envejecimiento y la composición corporal estudio [25], hecho en la Wake Forest University School of Medicine, los investigadores rastrearon la historia médica de los 2225 participantes para un promedio de 42 meses después de medir sus niveles en sangre de proteína C-reactiva, IL-6 y TNF-alfa. Las personas con los más altos niveles de IL-6 fueron de dos a cinco veces más probabilidad de tener un ataque al corazón, derrame cerebral u otros episodios cardiovasculares que aquellos con los niveles más bajos. Alto niveles sanguíneos de TNF-alfa aumentó el riesgo de enfermedades cardíacas en un 79 por ciento y de la insuficiencia cardiaca de 121 por ciento. Los altos niveles de proteína C reactiva aumentan el riesgo de insuficiencia cardiaca de 160 por ciento en comparación con aquellos con niveles bajos, pero no aumentar significativamente el riesgo de un primer accidente cerebrovascular o ataque al corazón.

Como era de esperar, la incidencia de las enfermedades cardiovasculares es elevada para las personas con los factores de riesgo convencionales - el hábito de fumar, presión arterial alta, colesterol alto y cosas por el estilo. Pero para los participantes libres de los factores de riesgo, la inflamación relacionados con las moléculas fueron mejores predictores de la enfermedad del corazón.

El metabolismo del colesterol

Normal adultos sanos sintetizar el colesterol a un ritmo de aproximadamente 1 g / día y consume aproximadamente 0,3 g / día. Un relativamente constante nivel de colesterol en el cuerpo (150 - 200 mg / dL) se mantiene en primer lugar por controlar los niveles de síntesis de novo. El nivel de colesterol síntesis está regulada en parte por la ingesta de colesterol. El colesterol de la dieta, tanto de síntesis y se utiliza en la formación de membranas y en la síntesis de las hormonas esteroideas y ácidos biliares. La mayor proporción de colesterol se utiliza en la síntesis de ácidos biliares [26]. Síntesis de colesterol se produce en el citoplasma y con microsomas inicial de mevalonate síntesis de las dos emisiones de carbono acetato grupo de acetil-CoA. Vea la Figura 1 (Mevalonate de síntesis).

1. Comienza en el momento de síntesis de acetil-CoA se deriva de una reacción de oxidación en la mitocondria y se transporta a el citoplasma

2. Dos moles de acetil-CoA se condensa, formando acetoacetyl-CoA. Acetoacetyl-CoA y un tercer lunar de acetil-CoA se convierten en 3-hidroxi-3-metilglutaril-CoA (HMG-CoA) por la acción de la HMG-CoA sintasa.

3. Inhibidores de la HMG-CoA se convierte en mevalonate, en una limitación de velocidad paso catalizado por la enzima HMG-CoA reductasa (HMGR)

En los seres humanos, el colesterol y isoprenoids luego se sintetizan a través de la vía mevalonate. Vea la Figura 2 (colesterol y Isoprenoid de síntesis).

1. Mevalonate se activa por tres sucesivos phosphorylations, produciendo 5-pyrophosphomevalonate

2. Después de fosforilación, ATP-dependiente descarboxilación rendimientos isopentenyl pirofosfato (IPP), una molécula activa isoprenoid. Isopentenyl pirofosfato se encuentra en equilibrio con su isómero, dimethylallyl pirofosfato, DMAPP.

3. Una molécula de la PPI se condensa con una molécula de DMAPP para generar geranilado pirofosfato (GPP). Este paso es catalizada por la sintetasa del GPP.

4. GPP más condensa con otra molécula de IPP a dar farnesyl pirofosfato (FPP). Este paso es catalizada por la sintetasa del FPP.

5. FPP condensa con otra molécula de IPP a dar geranylgeranyl pirofosfato (GGPP). Este paso es catalizada por la sintetasa GGPP

6. La cabeza a la cola de condensación de dos moléculas de FPP rendimiento escualeno, es catalizada por la escualeno sintetasa.

7. Escualeno se someten a un plan en dos etapas ciclación a dar lanosterol.

8. Lanosterol se convierte en colesterol, a través de una serie de 19 reacciones adicionales

Hay un complejo sistema de regulación de coordinar la biosíntesis de colesterol con la disponibilidad de colesterol dietético. La oferta de celulares de colesterol se mantenga a un nivel constante de los siguientes mecanismos:

1. Reglamento de HMGR y los niveles de actividad

2. Reglamento del exceso de colesterol libre intracelular a través de la actividad de acyl-CoA: colesterol acyltransferase (ACAT)

3. Reglamento de plasma a través de los niveles de colesterol LDL mediada por los receptores y la absorción de colesterol HDL mediado por revertir el transporte.

Interleukina 6

La interleucina-6 la familia de las citoquinas, la señalización a través de la subunidad del receptor común (glicoproteína), posteriormente se activa la señal transductores y activadores de transcripción (STAT3), mitogen-activated proteinkinase (MAPK), y phosphatidylinositol 3-kinasa (PI3K) [27]. La interleucina-6 (IL6), la familia comprende interleuquina (IL) -6, IL-11, factor inhibitorio de la leucemia, oncostatin M, factor neurotrófico ciliar y cardiotrophin-1. Entre sus muchas funciones, IL-6 desempeña un papel activo en la inflamación, inmunología, metabolismo óseo, la reproducción, la artritis, las neoplasias, y el envejecimiento. IL-6 expresión está regulada por una variedad de factores, entre ellos hormonas esteroides, tanto en el plano transcripcional y post-transcripcional. Niveles elevados de IL-6 se asocian con los más altos riesgos de enfermedad cardiovascular subclínica, así como para la clínica de enfermedades cardiovasculares en hombres y mujeres mayores [28]. Niveles elevados de IL-6 se asocia con un 34 por ciento mayor probabilidad de deterioro cognitivo en hombres mayores y mujeres [29]. Interleucina-6 inflamación mediada contribuye a la resorción ósea y la osteoporosis de osteoclastogenesis y estimular la actividad de los osteoclastos [30 - 32]. Interleuquina (IL) -6 producción es considerablemente mayor y más asociado con la destrucción ósea en Staphylococcus aureus y la artritis micobacteriana, osteítis u osteomielitis [33 - 35]. Durante épocas de estrés o depresión, niveles de IL-6 se incrementan. En un estudio de adultos mayores en un estrés crónico (hombres y mujeres que fueron cuidados por un cónyuge con demencia), de cuidadores tasa media de aumento de la IL-6 fue aproximadamente cuatro veces más grande que el de la no cuidadores [36, 37 ].

IL-6 transmite su señal biológica a través de dos proteínas en la célula. Una de ellas es la IL-6 receptor (IL-6R), un IL-6-molécula específica vinculante con un peso molecular de aproximadamente 80 kD. La otra es una membrana de proteína ligada al gp130 con un peso molecular de aproximadamente 130 kD que se dedica a ligando no-vinculante de transducción de señales. IL-6 receptor existe no sólo en la membrana de forma vinculada con el dominio de transmembrana expresada en la superficie celular, sino también como una soluble IL-6 receptor que consistían principalmente en la región extracelular. IL-6 e IL-6 receptor de la forma IL-6/IL-6 receptor complejo, que después de unirse a gp130 transmite su señal biológica para la célula. Los participantes importantes en la interleucina-6 señalización de la vía de incluir Janus quinasas (JAKs) Jak1, Jak2 y Tyk2, la señal de transductores y activadores de transcripción STAT1 y STAT3, la tirosina fosfatasa SHP2 [SH2 (homología Src 2) de dominio que contienen tirosina fosfatasa ] Y factor de transcripción NF-κ B.

Proteínas Quinasas

Engagementof superficie celular Interleukina-6 receptores activa la quinasa Janus (JAK) la familia de tirosina quinasas, lo que a su vez phosphorylate frente al citoplasma de la parte de gp130, lo que crea sitios de atraque para STAT factores STAT1 y STAT3 [38, 39]. Activado Estadísticas dimerize a la activación de JAKs y translocate al núcleo donde theybind de ADN específico los elementos de reacción y regular la expresiónde ciertos genes. Tras la dimerización de gp130, IL-6 activa múltiples vías de señalización (Ras MAP quinasa dependiente cascada, STAT1-STAT3 heterodimer vía, y STAT3 homodimer vía) [40 - 42].

Dimeric factores de transcripción

Activador de proteína-1 (AP-1) es un término colectivo para referirse dimeric factores de transcripción compuesto de Jun, Fos, o ATF (la activación de factor de transcripción) subunidades que se unen a la autopista AP-1 sitio de unión a los varios genes proinflamatorias incluyendo la IL - 6 promotor [43]. AP-1 actividad desempeña un papel importante en la respuesta inflamatoria de la modulación de la expresión génica de varios mediadores inflamatorios, incluyendo IL-6 transcripción. Fosforilación de c-Jun es un requisito previo de AP-1 dimerización y activación. AP-1 actividad está controlada por la señalización a través de la familia de JNK MAP quinasas. Se ha demostrado que durante la reperfusión, el estrés oxidativo conduce a la activación y translocación de JNK al núcleo, donde la fosforilación de factores de transcripción, tales como c-Jun ocurre.

Factor nuclear kappa B

Factor nuclear κ B (NF-κ B) es ampliamente expresada, inducible factor de transcripción de particular importancia para las células del sistema inmunológico. Originalmente fue identificado como un potenciador de la proteína de unión de la Ig-κ luz cadena de genes en células B [44]. NF-κ B regula la expresión de muchos genes involucrados en mamíferos inmune y respuestas inflamatorias, incluyendo citoquinas, moléculas de adhesión celular, factores de complemento, y una variedad de immunoreceptors. La NF-κ B, factor de transcripción es una proteína que heterodimeric comprende el P50 y p65 (Rel A) subunidades. Estas subunidades son proteínas de la familia Rel activadores de transcripción. Los miembros de la familia Rel comparten una conserva de 300 aminoácidos homología Rel dominio responsable de ADN obligatorio, la dimerización, y la localización nuclear. Aunque transcriptionally activa homodimers de ambos P50 y p65 pueden formar, la p50/65 heterodimer está formado preferentemente en la mayoría de tipos de células [45].

En ausencia de señales estimuladoras, el NF-κ B heterodimer se mantiene en el citoplasma de su físico asociación con un inhibidor phosphoprotein, κ B. Múltiples formas de I κ B han sido identificadas [46]. Dos de estas formas, me κ B α y β κ B, se ha demostrado que modulan la función de la NF-κ B heterodimer, y estas dos me Bs κ son fosforilados en respuesta a diferentes estímulos extracelulares [47]. Estudios recientes indican que la subunidad catalítica de la proteína quinasa A (PKA C) está asociada con el NF-κ B / I κ B α complejo [48]. En este p50/p65/I α κ B / C PKA tetrameric configuración, κ B α hace PKA C inactivos y máscaras de la señal de localización nuclear de NF-κ B. Proinflamatorias estímulos pueden activar una serie de proteínas cinasas, que tienen la capacidad de modular-factor nuclear κ B (NF-κ B) o activador de proteína-1 (AP-1). Una variedad de señales extracelulares estimulantes, como las citocinas, los virus, y de estrés oxidativo [49] activar quinasas que phosphorylate I κ B. Las citocinas activan I-κ B cinasa llamado IKK es la clave para la reglamentación quinasa I α κ B [50]. IkappaB quinasa (IKK) está compuesto por subunidades, IKK-alfa, IKK-beta y IKK-gamma, que son serina / treonina cinasas de proteínas cuya función es necesaria para NF-kappaB activación de pro-inflamatorias estímulos [51]. Fosforilación en serines 32 y 36 metas I κ B α para ubiquitination y posterior proteólisis rápida a través de un proteasoma mediada por vía [52 - 55], lo que resulta en la liberación de NF-κ B / C PKA. El ahora activa PKA C subunidad phosphorylates disocia y la subunidad p65 de NF-κ B. Fosforilados NF-κ B, entonces translocates al núcleo celular, donde se une al objetivo de secuencias en la cromatina y activa genes específicos subconjuntos, en particular los importantes para inmune inflamatoria y la función [56 - 58]. PPAR alfa (un proliferador de peroxisoma activados por los receptores alfa) interfiere negativamente con la expresión de genes inflamatorios por sobre regulación de la molécula inhibidor citoplásmico IkappaB alfa, por lo tanto, se crea una autoregulatory loop. Esta inducción se lleva a cabo en ausencia de un proliferador de peroxisoma-los elementos de reacción (PPRE), pero requiere la presencia de NF-kappaB y SP1 elementos en la IkappaB alfa secuencia promotora, así como cofactores DRIP250 [59].

Nuclear factor-kappaB (NF-kappaB) es un factor de transcripción para Ang II-inducible IL-6 expresión. Interleucina-6 (IL-6) se expresa de la angiotensina II (Ang II) estimulada vascular células musculares lisas (VSMCs). En un estudio Ang II inducida por el tratamiento IL-6 induce la transcripción de citoplásmica a la translocación nuclear del NF-kappaB subunidades Rel A y NF-kappaB1 paralelo con los cambios en el ADN vinculante actividad en una forma bifásica, que produjo un pico a principios de 15 minutos seguida de un nadir 1 a 6 horas más tarde y un pico más tarde a las 24 horas [60].

Proliferador de peroxisoma activados por Receptores (PPARs)

Proliferador de peroxisoma activados por los receptores (PPARs) son activados por ligando factores de transcripción que forman una subfamilia de receptores nucleares de la familia de genes. El PPAR subfamilia consta de tres isotipos, alfa (NR1C1), gamma (NR1C3), y beta / delta (NRC1C2) con una distribución diferencial de tejidos. PPARs son activados por ligandos, como la forma natural de ácidos grasos, que son activadores de PPAR los tres isotipos. Además de los ácidos grasos, varios compuestos sintéticos, tales como los fibratos y tiazolidindionas, y obligará a activar PPARalpha y PPARgamma, respectivamente. PPARalpha se expresa principalmente en los tejidos con un alto nivel de ácidos grasos catabolismo, como hígado, grasa marrón, riñón, corazón y músculo esquelético. PPARbeta se expresó doquier, y PPARgamma ha restringido patrón de expresión, principalmente en blanco y tejido adiposo pardo, mientras que otros tejidos como el músculo esquelético y el corazón contienen cantidades limitadas. Por otra parte, PPARalpha isotipos gamma y se expresan en las células vasculares y endoteliales incluidas células musculares lisas y macrófagos y células espumosas. Con el fin de ser transcriptionally activa, PPARs necesidad de heterodimerize con los retinoides-X-receptor (RXR). Tras la activación, PPAR-RXR heterodimers se unen a secuencias específicas de ADN llamada un proliferador de peroxisoma-los elementos de reacción (PPRE) y estimular la transcripción de genes objetivo. PPARs desempeñan un papel fundamental en los lípidos y la homeostasis de la glucosa, pero últimamente han sido implicados como reguladores de las respuestas inflamatorias. La primera evidencia de la participación de los PPARs en el control de la inflamación provenían de la PPARalpha null ratones, que se saldó con una respuesta inflamatoria prolongada. PPARalpha activación resulta en la represión de NF-kappaB señalización y la producción de citoquinas inflamatorias en diferentes tipos de células. Un papel para PPARgamma en la inflamación se ha observado también en los monocitos / macrófagos, donde ligandos de este receptor inhibe la activación de macrófagos y la producción de citoquinas inflamatorias (TNFalpha, interleucina 6 y 1beta) [61]. Activadores PPAR tener efectos tanto sobre los factores de riesgo metabólicos y en la inflamación vascular relacionados con la aterosclerosis. PPAR tienen profundos efectos sobre el metabolismo de las lipoproteínas y ácidos grasos. PPAR alfa se une fibratos hipolipemiantes, mientras que el PPAR gamma tiene una alta afinidad por los antidiabéticos glitazones. Ambos PPAR alfa y gamma son activados por ácidos grasos y sus derivados. La activación de PPAR alfa aumenta el catabolismo de los ácidos grasos en varios niveles. En el hígado, aumenta la absorción de ácidos grasos y su activa beta-oxidación. Los efectos que ejerce PPAR alfa en triglicéridos de las lipoproteínas ricas es debido a su estimulación de lipoproteína lipasa y la represión de la apolipoproteína CIII expresión, mientras que los efectos en las lipoproteínas de alta densidad dependerá de la regulación de apolipoproteinas AI y AII. PPAR gamma tiene profundos efectos en la diferenciación y la función del tejido adiposo, donde es altamente expresado. PPAR se expresa también en lesiones ateroscleróticas y están presentes en las células endoteliales vasculares, células musculares lisas, monocitos, los monocitos y macrófagos derivados. A través de la regulación negativa de factor nuclear kappa-B y activador de proteína-1 vías de señalización, PPAR alfa inhibe la expresión de genes inflamatorios, como la interleucina-6, la ciclooxigenasa-2, y la endotelina-1. Por otra parte, PPAR alfa inhibe la expresión de los monocitos de la contratación de las proteínas como vascular molécula de adhesión celular (VCAM) -1 e induce la apoptosis en los monocitos-macrófagos derivados. PPAR gamma de activación en los macrófagos y células espumosas inhibe la expresión de genes activados como inducible óxido nítrico sintasa, metaloproteasa de matriz extracelular-9 y A. scavenger receptor PPAR gamma también pueden afectar el reclutamiento de monocitos en lesiones ateroscleróticas, ya que está involucrada en la expresión de VCAM-1 y la molécula de adhesión intracelular-1 en las células endoteliales vasculares [62].

La activación de interleucina-6 inflamación de isoprenoids

Los receptores de citoquinas actúan a través de una compleja red de señalización GTPase la participación de las proteínas como Ras, Rho, el RAC, y Rab (en particular Rho), Janus quinasas (JAKs) y la señal de transductores y activadores de transcripción (Estadísticas) para regular diversos procesos biológicos controlar la función inmunológica , El crecimiento, el desarrollo y la homeostasis [63].

Isoprenoids son necesarios para la modificación postraduccional de lípidos (prenylation) y, por tanto, la función de Ras y otros pequeños triphosphatases guanosina (GTPasas) [64].

GTPase proteínas como Ras, Rho, el RAC, y Rab (en particular Rho) son proteínas de señalización intracelular que, cuando está activada, están involucrados en los receptores de acoplamiento de transducción de señales extracelulares de estímulos para el citoplasma y núcleo. Pequeños GTPase proteínas constituyen una superfamilia Ras, que está compuesto de al menos cinco grandes ramas. Los miembros de la rama Ras incluir el Ras, Rap, Ral y R-Ras familia de proteínas [65, 66]. La familia Ras regula la expresión génica. El Rho sucursal constituye una segunda gran rama, con RhoA, Rac1 y Cdc42 los miembros más estudiado. La familia Rho citoesqueleto regula la reorganización y la expresión génica. El Rab rama es la más grande y, junto con los miembros de la ARF / Sar rama, sirven como reguladores de transporte vesicular intracelular. Ran es el único miembro de su sucursal y es un elemento fundamental regulador de núcleo-citoplasma de transporte de proteínas y ARN. La superfamilia de proteínas Ras se alternan entre un inactivada PIB determinada forma activa y GTP-boundform, lo que les permite actuar como interruptores moleculares para el crecimiento y la diferenciación de las señales. Prenylation es un proceso que implica la unión de hidrofóbicas isoprenoid grupos de farnesyl o geranylgeranyl residuos a la C-terminal de la región superfamilia de proteínas Ras. Farnesyl pirofosfato (FPP) y Geranylgeranyl pirofosfato (GPP) son productos metabólicos de mevalonate que están en condiciones de la oferta prenyl grupos. El prenylation es llevada a cabo por prenyl transferases. El hidrofóbicas prenyl grupos son necesarios para asegurar la superfamilia Ras proteínas intracelulares a las membranas de manera que puedan ser trasladadas a la membrana plasmática [67]. El final de la membrana celular es necesaria la fijación de proteínas Ras a participar en sus interacciones [68, 69]. La actividad de los pequeños GTPase, Rac1, juega un papel importante en diversos procesos celulares incluyendo citoesqueleto reordenación, la transcripción de genes, y la transformación maligna. Pequeños GTPasas de la superfamilia de proteínas Ras estimular la fosforilación de la tirosina y la activación de JAK la familia de quinasas intracelulares. Esto, a su vez activa el STAT familia de factores de transcripción y los resultados en la inducción de la interleucina-6 y IL-6 gen receptor. La persistencia de Rac1 actividad conduce a la producción autocrina y transducción de señales de interleucina-6 [36]. IL-6 en sí puede producir un retraso en la fosforilación y la activación de STAT3, y JAK/STAT3 la vía indirecta es un objetivo de Ras y Rho GTPasas [70]. El bloqueo de la IL-6 inhibe la vía de señalización mediada por Rac1 que dependen de STAT3 la expresión génica. En un estudio [71], constitutivamente activa Rac1 (RAC V12) se muestra a estimular la activación de STAT3. La actividad de Rac1 lleva a STAT3 translocación al núcleo coincidiendo con STAT3 que dependen de la expresión génica [72]. Rac1 expresión resultados en la inducción de la IL-6 e IL-6 y los genes del receptor de anticuerpos neutralizantes dirigidos contra la IL-6 receptor bloque Rac1 inducida por la activación STAT3. La inhibición del factor nuclear-kappaB activación o interrupción de IL-6-señalización mediada a través de la expresión de IkappaBalpha S32AS36A y supresor de citocinas de señalización 3, respectivamente, bloques de Rac1 inducida por la activación STAT3. El estudio también investigó si los demás miembros de la familia Rho mediar STAT3 activación en un IL-6 dependiente de vía. La expresión de constitutivamente activa RhoG, Cdc42, RhoA y causó la translocación desde el citoplasma al núcleo de cotransfected STAT3-GFP. Este GTPase inducida STAT3 translocación fue bloqueada en diversos grados por la neutralización de IL-6 receptor de anticuerpos, el apoyo a una función autocrina de IL-6 en la familia Rho inducida por la activación STAT3. Estos hallazgos elucidar un mecanismo dependiente de la inducción de un autocrina de IL-6 a través de la activación de bucle que Rac1 y la familia Rho mediar STAT3 activación se establece un vínculo entre la actividad y GTPase Janus kinasa / STAT de señalización. Curiosamente, es la persistencia de STAT3 activada en muchos cánceres humanos y líneas de células transformadas. En cultivos celulares, activa STAT3 es necesaria ya sea para la transformación, aumenta la transformación, o bloquea la apoptosis.

En un estudio [73], leucemia de células de 50 pacientes con leucemia mieloide aguda (LMA) se analizaron para detectar la presencia de la activación de mutaciones puntuales de la N-RAS de genes usando reacción en cadena de polimerasa (PCR) y la hibridación diferencial de oligonucleótidos. La activación de clones de N-RAS, señaló en la gran mayoría de las células de leucemia el seis de estos pacientes, se correlacionó significativamente (p = 0.0003) con la capacidad de estas células para expresar interleucina 6 (IL-6), previamente a ser expresado en los niveles más altos en aproximadamente el 30% de las células primarias contra el blanqueo de dinero.

En resumen, isoprenoids farnesyl pirofosfato (FPP) y geranylgeranyl pirofosfato (GPP) son necesarios para la modificación postraduccional de lípidos (prenylation) y, por tanto, la función de Ras y otros pequeños GTPase proteínas como Ras, Rho, el RAC, y Rab [52] . Persistentemente activa de la familia Rho y Rac1 resultados en la activación de JAKs y posterior fosforilación de tirosina y la activación de STAT3 [74]. Tirosina fosforilados STAT3 formas dímeros que translocate al núcleo de obligar a los sitios objetivo de ADN en genes de respuesta [59]. IL-6 e IL-6 gen receptor de inducción se produce como resultado de activar las proteínas STAT y la IL-6 la media a largo plazo de activación de STAT3 a través de un bucle autocrina.

La inhibición del colesterol vía de las estatinas

El principal efecto de las estatinas es la disminución del nivel sérico de las lipoproteínas de baja densidad (LDL), debido a la inhibición de la biosíntesis de colesterol intracelular. Un menor efecto es la disminución de triglicéridos en suero. Statins inhibit HMG-CoA reductase and decrease the production of mevalonate, geranyl pyrophosphate, and farnesyl pyrophosphate, and subsequent products on the way to construction of the cholesterol molecule. Thus, statins could inhibit inflammation, by inhibition of the cholesterol pathway and intracellularly interfering with Ras superfamily protein function [ 75 ]. Ikeda et al . [ 76 ] recently showed that statins decrease matrix metalloproteinase-1 expression through inhibition of Rho. Statin therapy has been demonstrated to provide significant reductions in non-high-density lipoprotein cholesterol, and to decrease cardiovascular morbidity and mortality.

Inhibition of cholesterol pathway by bisphosphonates

Recent findings suggest that alendronate and other N-containing bisphosphonates inhibit the isoprenoid biosynthesis pathway and interfere with protein prenylation, as a result of reduced geranylgeranyl diphosphate levels. One study [ 77 ] utilizing High-performance liquid chromatography (HPLC) analysis of products from a liver cytosolic extract, identified farnesyl disphosphate (FPP) synthase as the mevalonate pathway enzyme inhibited by bisphosphonates. Recombinant human farnesyl diphosphate synthase was inhibited by alendronate with an IC(50) of 460 nM (following 15 min preincubation). Alendronate did not inhibit isopentenyl diphosphate isomerase or GGPP synthase. Recombinant farnesyl diphosphate synthase was also inhibited by pamidronate (IC(50) = 500 nM) and risedronate (IC(50) = 3.9 nM), negligibly by etidronate (IC50 = 80 microM), and not at all by the non-nitrogen-containing bisphosphonate clodronate. In another study, a wide range of bisphosphonates, were found to have a significant correlation between potency for inhibition of recombinant human FPP synthase in vitro and anti-resorptive potency in vivo , suggesting that this enzyme is the major pharmacologic target of these drugs. The most potent anti-resorptive bisphosphonates such as zoledronic acid and risedronate are very potent inhibitors of FPP synthase, with IC50 values as low as 3 nM and 10 nM respectively. Inhibition of FPP synthase prevents the formation of FPP and its derivative GGPP. These isoprenoid lipids are necessary for the post-translational lipid modification (prenylation) of small GTPase proteins such as Ras, Rho, Rac, and Rab. The effects of nitrogen-containing bisphosphonates on osteoclasts can be overcome by addition of components of the mevalonate pathway, which bypass the inhibition of FPP synthase and restore protein prenylation. In particular, geranylgeraniol (a cell-permeable form of GGPP) prevents inhibition of resorption by nitrogen-containing bisphosphonates in vitro [ 78 ].

Fungi, plant-derived polyphenolic compounds and fatty acids

Statins identical to the cholesterol lowering pharmaceutical lovastatin and its derivatives of simvastatin, pravastatin and mevastatin can be produced by a variety of filamentous fungi, including Monascus, Aspergillus, Penicillium, Pleurotus, Pythium, Hypomyces, Paelicilomyces, Eupenicillium, and Doratomyces [ 79 ]. As a food product, rice fermented with a red Monascus fungus (red rice) has been known to contain low amounts of statins and used for hundreds of years in China. Red rice is used in wine making, as a food-coloring agent and as a drug in traditional Chinese medicine.

Several hundred molecules having a polyphenol (polyhydroxyphenol) structure (ie several hydroxyl groups on aromatic rings) have been identified in edible plants. These molecules are secondary metabolites of plants and are generally involved in defense against ultraviolet radiation or aggression by pathogens. Polyphenols are widespread constituents of fruits, vegetables, cereals, dry legumes, chocolate, and beverages, such as tea, coffee, or wine. These compounds may be classified into different groups as a function of the number of phenol rings that they contain and of the structural elements that bind these rings to one another. Classes of polyphenols include the phenolic acids, flavonoids, stilbenes, and lignans. There are two classes of phenolic acids: derivativesof benzoic acid and derivatives of cinnamic acid.

Hydroxybenzoic acids are components of complex structures such as hydrolyzable tannins (gallotanninsin mangoes and ellagitannins in red fruit such as strawberries, raspberries, and blackberries). Hydroxycinnamic acids are more common than are the hydroxybenzoicacids and consist chiefly of p -coumaric, caffeic, ferulic, and sinapic acids. Caffeic and quinic acid combine to form chlorogenic acid, whichis found in many types of fruit and in high concentrations in coffee.

Flavonoids, are the largest single class as far as total numbers of known compounds. About two-thirds of the polyphenols we obtain in our diets are flavonoids. Flavonoids share a common structure consisting of 2 aromatic rings that are bound together by 3 carbon atoms that form an oxygenated heterocycle, and may be divided into 6 major subclasses: Anthocyanidins (eg, cyanidin, pelargonidin); Flavanols (eg, epicatechin, gallocatechin); Flavones (eg, apigenin, luteolin); Flavonols (eg, kaempferol, myricetin, quercetin); Flavanones (eg, hesperidin, naringenin); Isoflavones (eg, genistein, daidzein, biochanin) and Proanthocyanidins [ 80 ].

Proanthocyanidins (condensed tannins) are a class of polyphenolic compounds found in several plant species. They include procyanidins, which are chains of catechin, epicatechin, and their gallic acid esters and the prodelphinidins, which consist of gallocatechin, epigallocatechin, and their gallic acid esters as the monomeric units.

Isoflavones are flavonoids with structural similarities to estrogens. Although they are not steroids, they have hydroxyl groups in positions 7 and 4 in a configuration analogous to that of the hydroxyls in the estradiol molecule. This confers pseudohormonal properties on them, including the ability to bind to estrogen receptors, and they are consequently classified as phytoestrogens. Phytoestrogenic isoflavones including genistein, daidzein, glycitein, biochanin A, formononetin, and their respective naturally occurring glycosides and glycoside conjugates are found in plants such as legumes, clover, and the root of the kudzu vine (pueraria root). Common legume sources of these isoflavone compounds include soy beans, chick peas, ground nuts, lentils and various other types of beans and peas. Clover sources of these isoflavone compounds include red clover and subterranean clover.

Fatty acids consist of chains of carbon atoms linked together by chemical bonds. Fatty acids come in different lengths: short chain fatty acids have fewer than 6 carbons, while long chain fatty acids have 12 or more carbons. On one terminal of the carbon chain is a methyl group and on the other terminal is a carboxyl group. The chemical bonds between the carbon atoms determine whether a fatty acid is saturated or unsaturated. Saturated fatty acids contain single bonds only. Examples of foods high in saturated fats include lard, butter, whole milk, cream, eggs, red meat, chocolate, and solid shortenings. An excess intake of saturated fat can raise blood cholesterol and increase the risk of developing coronary heart disease. Monounsaturated fatty acids contain one double bond. Examples of foods high in monounsaturated fat include avocados, nuts, and olive, peanut, and canola oils. Polyunsaturated fatty acids contain more than one double bond. Examples of foods high in polyunsaturated fats include vegetable oils, corn, sunflower, and soy. Essential fatty acids are polyunsaturated fatty acids that the human body needs for metabolic functioning but cannot produce, and therefore has to be acquired from food. Omega-3 fatty acids are a class of essential polyunsaturated fatty acids with the double bond in the third carbon position from the methyl terminal (hence the use of "3" in their description). Foods high in omega-3 fatty acids include cold-water fatty fish such as salmon, herring, mackerel, anchovies and sardines, and vegetable sources such as the oil from the seeds of chia, perilla, flax, purslane, hemp, and canola. Other foods that contain omega-3 fatty acids include whole grains, beans, green leafy vegetables such as spinach and seafood such as shrimp, clams, light chunk tuna, catfish and cod. Omega-6 fatty acids are a class of essential polyunsaturated fatty acids with the initial double bond in the sixth carbon position from the methyl group. Examples of foods rich in omega-6 fatty acids include corn, safflower, sunflower, soybean, and cottonseed oil. Omega-3 and omega-6 fatty acids are also referred to as n-3 and n-6 fatty acids, respectively.

Atherosclerosis and Interleukin 6

Macrophage uptake of oxidized low-density lipoprotein (Ox-LDL) is a hallmark of the early atherosclerotic lesion, and may be mediated by Interleukin-6. Incubation of IL-6 with MPM or IL-6 administration in mice increased macrophage Ox-LDL degradation and CD36 mRNA expression. Angiotensin II (Ang II) plays an important role in atherogenesis. Ang II increases macrophage cholesterol accumulation and foam cell formation, increases contraction of blood vessels and induces hypertrophyand hyperplasia of vascular smooth muscle cells (VSMC). Ang II significantly increases the expression of IL-6 mRNA and protein in vascular smooth muscle, in a dose-dependent manner. The induction of IL-6 expression by Ang II is dependent on intracellular Ca 2+ , tyrosine phosphorylation, and mitogen-activated proteinkinase (MAPK)[ 81 ]. Ang II administration to apolipoprotein E-deficient atherosclerotic mice increases Ox-LDL degradation, CD36 mRNA expression, and CD36 protein expression by their peritoneal macrophages (MPMs). Ang II treatment of IL-6-deficient mice did not affect their MPM Ox-LDL uptake and CD36 protein levels. Furthermore, injection of IL-6 receptor antibodies in mice during Ang II treatment reduced macrophage Ox-LDL uptake and CD36 expression [ 82 ].

Enzymatic, nonoxidative modification transforms low density lipoprotein (LDL) to an atherogenic molecule (E-LDL) that activates complement and macrophages and is present in early atherosclerotic lesions. E-LDL accumulates in human vascular smooth muscle cells (VSMC), where it stimulates the expression of gp130, the signal-transducing chain of the IL-6 receptor (IL-6R) family, and the secretion of Interleukin-6 [ 83 ]. IL-6/sIL-6R provokes marked up-regulation of gp130 mRNA and surface protein expression in VSMC. This is accompanied by secretion of IL-6 by the cells, so that an autocrine stimulation loop is created. In the wake of this self-sustaining system, there is a selective induction and secretion of monocyte chemotactic protein-1 (MCP-1), up-regulation of ICAM-1, and marked vascular smooth muscle proliferation [ 84 ]. Interleukin-6 (IL-6) induces proliferation of vascular smooth muscle cells and the release of monocyte chemoattractant protein-1 (MCP-1) [ 85 ]. One study investigated IL-6 mRNA expression in atherosclerotic arteries from patients undergoing surgical vascularization, utilizing reverse transcription polymerase chain reaction (RT-PCR) and in situ hybridization analyses. In RT-PCR analysis, the atherosclerotic arteries showed 10- to 40-fold levels of IL-6 mRNA expression over the non-atherosclerotic artery. In in-situ hybridization analysis, IL-6 gene transcripts were observed in the thickened intimal layer of atherosclerotic lesions. These results strongly suggest the involvement of IL-6 in the development of human atherosclerosis [ 86 ]. Thrombin is a potent mitogen for vascular smooth muscle cells (VSMCs) and plays an important role in the progression of atherosclerosis. Thrombin induces IL-6 mRNA and protein expression in a dose-dependent manner. Pharmacological inhibition of extracellular signal-regulated protein kinase (ERK), p38 mitogen-activated protein kinase (MAPK), or epidermal growth factor receptor (EGF-R) suppresses thrombin-induced IL-6 expression [ 87 ]. IL-6 increases the number of plateletsin the circulation [ 88 ] and activates platelets through arachidonic acid metabolism in vitro [ 89 ] IL-6 is reported to increaseplasma fibrinogen and decrease free protein S concentration. These IL-6-induced modifications of platelet and the coagulant phase of the clotting mechanism may lead to pathological thrombosis and instability of plaque [ 90 ]. IL-6 stimulation of vascular smooth muscle cells occurs via the JAK/STAT signaling pathway. In one study, Rat VSMC were stimulated with IL-6 in the presence or absence of a JAK 2 inhibitor, and the activation of STAT 3 (by Western), MCP-1 (by ELISA) and DNA synthesis (by (3)H-thymidine incorporation) was determined. IL-6 rapidly induced phosphorylation of STAT 3 in a dose- and time-dependent manner with a peak expression at 30 min. IL-6 also stimulated MCP-1 protein production and DNA synthesis dose dependently. 50 microM of AG490, a specific JAK 2 inhibitor, partially inhibited STAT 3 activation and MCP-1 production, with near complete inhibition of DNA synthesis [ 91 ]. Levels of IL-6 are significantly higher in patients with dyslipidemia IIa and IIb biochemically confirmed, and IL-6 levels are significantly correlated to intima-media complex thickness [ 92 ].

Statins and Interleukin 6

The ability of HMG-CoA reductase inhibitors to lower C-reactive protein levels has recently brought into question the mechanisms of action of the statin drugs. Because these medications lower incidences of acute cardiovascular events as well as decreasing morbidity and mortality well before the effects of lowered LDL cholesterol can be expected to occur, questions have been asked about whether they may work independently of LDL-lowering mechanisms. One study examined the effects of atorvastatin on soluble adhesion molecules, interleukin-6 (IL-6) and brachial artery endothelial-dependent flow mediated dilatation (FMD) in patients with familial (FH) and non-familial hypercholesterolemia (NFH) [ 93 ]. A total of 74 patients (27 FH and 47 NFH) were recruited. Fasting lipid profiles, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular-cellular adhesion molecule-1 (sVCAM-1), E-selectin, IL-6 and FMD were measured at baseline, 2 weeks, 3 and 9 months post-atorvastatin treatment (FH – 80 mg/day, NFH – 10 mg/day). In both groups, compared to baseline, sICAM-1 levels were significantly reduced at 2 weeks, further reduced at 3 months and maintained at 9 months (P < 0.0001). The IL-6 levels were significantly reduced at 3 months and 9 months compared to baseline for FH (P < 0.005) and NFH (P < 0.0001). In both groups, the FMD at 2 weeks was higher than baseline (P < 0.005), with progressive improvement up to 9 months. FMD was negatively correlated with sICAM-1 and IL-6.

Bisphosphonates and Interleukin 6

Because of various modes of action observed in studies, bisphosphonates have been classified into two groups. Bisphosphonates (such as clodronate and etidronate) that closely resemble pyrophosphate – a normal byproduct of human metabolism – are incorporated into adenosine triphosphate (ATP) analogues, which create compounds that are believed to build up and lead to osteoclast death [ 94 ]. The newest generation of bisphosphonates, which contain nitrogen (such as pamidronate, alendronate, risedronate, and ibandronate), are believed to inhibit protein prenylation (post-translational modification) within the mevalonate pathway. The mevalonate pathway is responsible for the biosynthesis of cholesterol, other sterols, and isoprenoid lipids. Isoprenoid lipids are key in the prenylation of intracellular signaling proteins (GTPases) that, when activated, regulate a number of processes, including osteoclast activity. It is believed that by impeding the function of these regulatory proteins, bisphosphonates block osteoclast functioning and cause apoptosis [ 95 ].

In patients with Paget's disease of bone, bisphosphonate therapy is associated with a significant reduction of Interleukin-6 soluble receptor (sIL-6R) serum levels [ 96 ]. Bisphosphonates inhibit the production of pro-inflammatory cytokine interleukin-6 in tumoral cell lines of human osteoblastic phenotype (MG63 and SaOs cells), and in peripheral blood mononuclear cells (PBMC) [ 97 ]. Bisphosphonates also inhibit IL-1 and TNF-alpha stimulated IL-6 release in cultures of human osteoblastic osteosarcoma cells [ 98 ]. Osteoblasts exposed to small amounts of bisphosphonate elaborate a soluble inhibitor, which interferes with osteoclast formation and development [ 99 ]. Bisphosphonates prevent apoptosis of murine osteocytic MLO-Y4 cells, whether it is induced by etoposide, TNF-alpha, or glucocorticoid dexamethasone [ 100 ]. Pamidronate and other bisphosphonates inhibit the production by osteoblasts of the inflammatory cytokine interleukin-6, a growth factor essential to myeloma cells [ 101 ].

Plant polyphenols, fatty acids and Interleukin 6

The beneficial skeletal effects of genistein, at dietarily achievable levels, are mediated, by Interleukin-6. Interleukin-6 production was decreased 40% to 60% in osteoblastic cells treated with genistein from either day 8–16 or day 12–16, at dietarily achievable concentrations (10(-10) to 10(-8) M) (P < 0.05) [ 102 ]. In one study, Sophoricoside (SOP) an isoflavone glycosid isolated from immature fruits of Sophora japonica (Leguminosae family) inhibited the interleukin (IL)-6 bioactivity with an IC50 value of 6.1 microM [ 103 ]. In another study, treatment with soybean isoflavones (10(-5) M), in the presence of TNF-alpha (10(-10) M), for 48 h inhibited production of IL-6 and PGE(2). The authors suggested that the antiresorptive action of soy phytoestrogen may be mediated by decreases in these local factors [ 104 ]. One study investigated the mechanisms of drug resistance associated with the human prostate carcinoma PC-3 cell line. Endogenous and exogenous IL-6 and exogenous OM up-regulated cell growth and enhanced resistance of PC-3 tumor cells to both etoposide and cisplatin. Both IL-6- and OM-mediated effects were inhibited by the treatment of PC-3 with an antisense oligodeoxynucleotide against gp130, the protein kinase inhibitor genistein (GNS), or the monoterpene perillic acid (PA), a posttranslational inhibitor of p21ras isoprenylation [ 105 ]. In another study, the effect of inhibition of tyrosine kinase activity on thymidine uptake into cultured human pituitary adenoma cells was studied using two inhibitors, genistein and methyl-2,3-dihydroxycinnamate (MDHC). Of 33 pituitary adenomas, 7 incorporated sufficient [3H]thymidine to be investigated in the experiments. Genistein and MDHC both potently inhibited thymidine uptake into these tumors, with a mean inhibition by 74 mumol/L genistein of 61.96 +/- 18.96% (+/- SD inhibition of basal), by 740 mumol/L genistein of 92.65 +/- 8.59%, and by 100 mumol/L MDHC of 93.84 +/- 3.85%. Epidermal growth factor stimulated thymidine uptake in 2 of the 3 clinically nonfunctioning adenomas studied, and this stimulation was inhibited by genistein. The authors concluded that tyrosine kinase activity is crucial for the integrity and growth of pituitary adenomas in culture and that growth factors released by pituitary adenomas potentially may maintain and promote tumor growth by stimulating tyrosine kinase activity [ 106 ].

Bacterial LPS induce a 12- to 16-fold increase in IL-1 beta, IL-6, and TNF-alpha mRNA levels. In one study, this increase was completely or more than 80% blocked by the protein tyrosine kinase specific inhibitors herbimycin A and genistein at the concentrations of 1.7 and 37 microM, respectively. LPS-induced IL-6 protein synthesis and IL-6 bioactivity were also reduced to baseline levels by the PTK inhibitors herbimycin A and genistein. Both PTK inhibitors also reduced the LPS activation of nuclear factor-kappa B (NF-kappa B), which is a transcription factor involved in the expression of cytokine genes such as IL-6 and TNF-alpha [ 107 ].

Epidemiological evidence suggests that tea consumption may have a strong effect on cardiovascular disease, but there has been no prior description of the molecular mechanisms involved. Epigallocatechin-3-gallate (EGCG) is a prominent catechin present in green tea. Several experimental studies have reported beneficial effects of EGCG in inflammation and cancer [ 108 - 110 ]. NF-κB, is a transcription factor centrally involved in the signal transduction of the inflammatory process. The common pathway for activation of NF-κB involves phosphorylation of its inhibitor protein IκB-α by IKK. Activation of IKK complex is an essential step for NF-κB activation because the kinase phosphorylates IκB-α and allow its degradation. Several studies have demonstrated that EGCG is an effective inhibitor of IKK activity. EGCG inhibits TNF-α-mediated IKK activation in human epithelial cells. Yang and colleagues showed that EGCG in concentrations of 50 to 200 μM inhibited IKK activity in an intestinal epithelial cell line [ 111 ]. In the Myocardial ischemia reperfusion study, EGCG reduced reperfusion-induced activation of IKK, degradation of IκB-α, and activation of NF-κB [ 112 ]. EGCG has been demonstrated to dramatically inhibit chemokine induced neutrophil chemotaxis in vitro [ 113 ]. Tea polyphenols have also been noted to induce apoptosis and cell cycle arrest in a wide array of cell lines [ 114 - 116 ]. EGCG affects several signaling mechanisms in inflammation. Menegazzi and colleagues showed that interferon-γ-induced STAT-1 activation in carcinoma-derived cell lines of non-gut origin was blocked by EGCG [ 117 ]. In another study, Watson and colleagues demonstrated that EGCG significantly reduced INF-γ-induced STAT1 activation in T84 epithelial and THP-1 monocytes/macrophages [ 118 ].

Polyunsaturated omega-3 fatty acids reduce the secretion of proinflammatory cytokines and down regulate the inflammatory process. 18-week n-3 PUFA diet supplementation exerts a significant inhibitory effect on basal and lipopolysaccharide (LPS)-stimulated IL-6 monocyte production (50% and 46%, respectively, P < 0.05) [ 119 , 120 ].

Atherosclerosis and statins

Changes in intima-media thickness (IMT) and arterial lumen diameter-as measured by B-mode high-resolution ultrasonography and quantitative coronary angiography, respectively-are currently the only surrogate markers for progression of atherosclerotic disease. There has been increasing use of this imaging technique in observational studies and interventional studies of lipid-lowering agents over the last decade. These observational studies clearly demonstrated an association between carotid IMT and atherosclerotic disease. Of the interventional studies, the recent Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) trial found that use of atorvastatin 80 mg daily for aggressive lowering of plasma low-density lipoprotein cholesterol (LDL-C) concentrations to below current target levels was associated with significant IMT regression compared with results obtained with less aggressive plasma LDL-C lowering [ 121 , 122 ].

Atherosclerosis and bisphosphonates

In one study the effect of etidronate treatment on carotidarterial intima-media thickness was prospectively examined in 57 subjects with type 2 diabetes associated with osteopenia. After 1 yr of therapy with cyclical etidronate (200 mg/day for 2 weeks every 3 months), intima-media thickness showed a decrease (mean ± SE, -0.038 ± 0.011 mm), which was significantly different from a change in 57 control subjects (0.023 ± 0.015 mm; P < 0.005). Cardiovascular parameters were not changed after etidronate treatment. The authors concluded that etidronate in clinical dosage may have an antiatherogenic action, at least in type 2 diabetes [ 123 ]. In another study, administration of ethane-1-hydroxy-1,1-diphosphonate (EHDP) to swine with pre-established atherosclerosis resulted in lower lesion calcium concentration, smaller lesions and a decrease in the area of lesions involved in necrosis [ 124 ].

Atherosclerosis, plant polyphenols and fatty acids

Cupric-ion-oxidized LDL (CuLDL) or endothelial cell-oxidized LDL (ELDL) induces the activation by Tyr-phosphorylation of JAK2, one of the Janus kinase involved upstream of STATs in the JAK/STAT pathway of cytokine transduction. Oxidized LDL (OxLDL) also initiates STAT1 and STAT3 Tyr-phosphorylation and translocation to the nucleus, with a more marked effect for the extensively modified CuLDL. In one study, Genistein, a nonspecific Tyr-kinase inhibitor, and AG490, a specific inhibitor of JAKs, markedly prevented the CuLDL-induced enhancement of STAT1 and STAT3 Tyr-phosphorylation and DNA-binding activity, suggesting that JAKs are the main kinases involved in STATs' activation by oxidized LDL [ 125 ]. The effect of genistein on aortic atherosclerosis was studied in New Zealand White rabbits. After provocation of atherosclerosis with hyperlipidemic diet, the rabbits were divided as hyperlipidemic diet group (HD), normal diet group (ND) and hyperlipidemic plus genistein diet group (HD + genistein) for 4 and half months. The average cross sectional area of atherosclerotic lesion was 0.269 mm2 after provocation. The lesion was progressed by continuous hyperlipidemic diet (10.06 mm2) but was increased mildly by genistein (0.997 mm2), and decreased by normal diet [ 126 ]. Angiotensin II (Ang II) plays an important role in atherogenesis. One study investigated the effect of Ang II on the production of interleukin-6 (IL-6) in rat vascular smooth muscle cells. Ang II significantly increased the expression of IL-6 mRNA and protein in a dose-dependent manner (10(-10) to 10(-6) mol/L). The expression of IL-6 mRNA induced by Ang II was completely blocked by an Ang II type 1 receptor antagonist, CV11974. Inhibition of tyrosine kinase with genistein, and inhibition of mitogen-activated protein kinase with PD98059 completely abolished the effect of Ang II [ 127 ]. The potent endothelium-derived vasoactive factor endothelin-1 (ET-1) has been implicated in the pathophysiology of atherosclerosis and its complications. ET-1 stimulates the formation of proinflammatory cytokines including Interleukin-6 and tumor necrosis factor alpha (TNF alpha) [ 128 ]. In one study ET-1 transiently increased IL-6 mRNA compatible with regulation of IL-6 release at the pretranslational level. Electrophoretic mobility shift assays demonstrated time- and concentration-dependent activation of the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) in ET-1-stimulated human vascular SMC. A decoy oligodeoxynucleotide bearing the NF-kappaB binding site inhibited ET-1-stimulated IL-6 release to a great extent suggesting that this transcription factor plays a key role for cytokine production elicited by ET-1 [ 129 ].

Type 2 diabetes and Interleukin 6

Circulating levels of interleukin-6 (IL-6) are raised in insulin resistant states such as obesity, impaired glucose tolerance (IGT), and type 2 diabetes mellitus (DM). Growing evidence suggests that IL-6 is not only produced by fat cells but is also capable of inducing insulin resistance in these cells. The expected result of this in vivo, would be to increase adipose mass and subsequently body mass index (BMI). The IL-6 -174G > C common functional gene variant has consistently been associated with increased plasma IL-6, insulin resistance, and increased cardiovascular risk [ 130 ]. In The Women's Health Study (an ongoing US primary prevention, randomized clinical trial initiated in 1992), the authors determined whether elevated levels of the inflammatory markers interleukin 6 (IL-6) and C-reactive protein (CRP) are associated with development of type 2 DM in healthy middle-aged women. From a nationwide cohort of 27 628 women free of diagnosed DM, cardiovascular disease, and cancer at baseline, 188 women who developed diagnosed DM over a 4-year follow-up period were defined as cases and matched by age and fasting status with 362 disease-free controls. Study results showed that baseline levels of IL-6 (P < .001) and CRP (P < .001) were significantly higher among cases than among controls. The relative risks of future DM for women in the highest vs lowest quartile of these inflammatory markers were 7.5 for IL-6 (95% confidence interval [CI], 3.7–15.4) and 15.7 for CRP (95% CI, 6.5–37.9). Positive associations persisted after adjustment for body mass index, family history of diabetes, smoking, exercise, use of alcohol, and hormone replacement therapy. The authors concluded that elevated levels of CRP and IL-6 predict the development of type 2 DM, and the data support a possible role for inflammation in diabetogenesis.

Type 2 diabetes and bisphosphonates

Advanced glycation end products (AGE), senescent macroprotein derivatives form at an accelerated rate in diabetes and induce angiogenesis through overgeneration of autocrine vascular endothelial growth factor (VEGF). In one study, incadronate disodium, a nitrogen-containing bisphosphonate, was found to completely inhibit AGE-induced increase in DNA synthesis as well as tube formation of human microvascular endothelial cells (EC). Furthermore, incadronate disodium significantly prevented transcriptional activation of nuclear factor-kappaB and activator protein-1 and the subsequent up-regulation of VEGF mRNA levels in AGE-exposed EC. Farnesyl pyrophosphate, but not geranylgeranyl pyrophosphate, was found to completely reverse the anti-angiogenic effects of incadronate disodium on EC. These results suggest that incadronate disodium could block the AGE-signaling pathway in microvascular EC through inhibition of protein farnesylation [ 131 , 132 ]. In another study, the bisphosphonate, pamidronate, given as a single dose led to a reduction in bone turnover, symptoms and disease activity in diabetic patients with active Charcot neuroarthropathy [ 133 ].

Type 2 diabetes and statins

In West of Scotland Coronary Prevention Study (WOSCOPS) [ 134 ], development of type 2 diabetes mellitus (DM) was found to decrease by 30% in pravastatin-treated patients. One study investigated the effects of an HMG-CoA reductase inhibitor, atorvastatin, on insulin sensitization in performed in chow fed Zucker lean and fatty rats treated with atorvastatin 50 mg/kg/day (ATORVA_50) and results were compared to Zucker lean and fatty rats treated with drug vehicle only (CONT). Treatment with atorvastatin resulted in a dose-dependent improvement in whole body insulin sensitivity in both lean and fatty rats, with an approximately two-fold increase in glucose infusion rate and glucose disposal (Rd) in ATORVA_50 versus CONT (p < 0.01) [ 135 ]. Another study investigated the effects of atorvastatin on the glucose metabolism and insulin resistance of KK/Ay mice, an animal model of type 2 diabetes, were investigated. Atorvastatin significantly decreased the non-HDL-cholesterol level in the oral glucose tolerance test, inhibited increase in the 30-min glucose level, decreased plasma insulin levels before and 30 and 60 minutes after glucose loading, and decreased the insulin resistance index, compared with corresponding values in controls, indicating that atorvastatin appeared to improve glucose metabolism by improving insulin resistance [ 136 ].

Type 2 diabetes, plant polyphenols and fatty acids

Nutritional intervention studies performed in animals and humans suggest that the ingestion of soy protein associated with isoflavones and flaxseed rich inlignans improves glucose control and insulin resistance. In animal models of obesity and diabetes, soy protein has been shown to reduce serum insulin and insulin resistance. In studies of human subjects with or without diabetes, soy protein also appears to moderate hyperglycemia and reduce body weight, hyperlipidemia, and hyperinsulinemia, supporting its beneficial effects on obesity and diabetes [ 137 ]. Recent studies have provided evidence that soy consumption alleviates some of the symptoms associated with Type 2 diabetes such as insulin resistance and glycemic control [ 138 , 139 ]. Isoflavones may improve lipid and glucose metabolism by acting as an antidiabetic PPAR agonist [ 140 ] The beta subunit of the signalsome – IKKbeta, a crucial catalyst of NF-kappaB activation – is an obligate mediator of the disruption of insulin signaling induced by excessive exposure of tissues to free fatty acids and by hypertrophy of adipocytes. IKKbeta plays a crucial role, not only in the induction of insulin resistance, but also atherogenesis, a host of inflammatory disorders, and the survival and spread of cancer. The polyphenols resveratrol and silibinin. inhibit or suppress the activation of IKKbeta [ 141 ]. Epidemiologic studies have reported a lower prevalence of impaired glucose tolerance and type 2 diabetes in populations consuming large amounts of the n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) found mainly in fish [ 142 ].

Osteoporosis and Interleukin 6

Osteoporosis is a condition that is common with aging and especially in post-menopausal women. The etiology has often been ascribed to abnormalities in calcium metabolism. However many patients with osteopenia/osteoporosis have in common pain and inflammation and many inflammatory pain syndromes have osteopenia/osteoporosis as an accompanying feature [ 143 ]. Inflammatory joint disease, particularly rheumatoid arthritis [ 144 ], is associated with bone resorption and increased synovial fluid levels of IL-6 [ 145 ]. Another example is the osteoporosis that is often present in Complex Regional Pain Syndrome/Reflex sympathetic dystrophy (CRPS-I/RSD) [ 146 ]. Interleukin-6 mediated inflammation has been shown to contribute to the process of bone remodeling. This it does by stimulating osteoclastogenesis and osteoclast activity [ 147 ]. Elevated levels of Interleukin-6 have been observed in conditions of rapid skeletal turnover and hypercalcemia as in Paget's disease and multiple myeloma [ 148 ]. In multiple myeloma, radiologic examinations reveals osteolytic lesion and the most common finding is diffuse osteopenia [ 149 ]. Adhesion of multiple myeloma cells to stromal cells triggers IL-6 secretion by the stromal cells [ 150 ]. This results in increased osteoclastic activity that in turn results in osteoporosis, painful osteolytic lesions and hypercalcemia characteristic of multiple myeloma [ 151 ]. In their youth, women are protected from osteoporosis because of the presence of sufficient levels of estrogen. Estrogen blocks the osteoblast's synthesis of Interleukin 6. Estrogen may also antagonize the interleukin 6 receptors. Decline in estrogen production is often associated with osteopenia/osteoporosis in postmenopausal women. Estrogen's ability to repress IL-6 expression was first recognized in human endometrial stromal cells [ 152 ]. Additional clues came from the observations that menopause or ovariectomy resulted in increased IL-6 serum levels [ 153 ], increased IL-6 mRNA levels in bone cells [ 154 ], and increased IL-6 secretion by mononuclear cells [ 155 - 157 ]. Further evidence for estrogen's ability to repress IL-6 expression is derived from studies, which demonstrated that estradiol inhibits bone marrow stromal cell and osteoblastic cell IL-6 protein and mRNA production in vitro [ 158 ] and that estradiol was as effective as neutralizing antibody to IL-6 in suppressing osteoclast development in murine bone cell cultures [ 159 ]or in ovariectomized mice [ 160 ].

Osteoporosis and bisphosphonates

Bisphosphonates are inorganic chemical compounds that bind to hydroxyapatite in bone and prevent osteoclastic absorption of bone. Nitrogen-containing bisphosphonates (N-BPs) are potent inhibitors of bone resorption widely used in the treatment of osteoporosis and other bone degrading disorders including Paget's disease of bone, hypercalcemia associated with malignancy, metastatic bone diseases, such as breast cancer, multiple myeloma, and arthritis [ 161 , 162 ]. At the tissue level, N-BPs reduce bone turnover and increase bone mass and mineralization. This is measured clinically as an increase in bone mineral density and bone strength and a decrease in fracture risk. N-BPs localize preferentially at sites of bone resorption, where mineral is exposed, are taken up by ostoclasts and inhibit osteoclastic activity. At the molecular level, N-BPs inhibit an enzyme in the cholesterol synthesis pathway, farnesyl diphosphate synthase. As a result, there is a reduction in the lipid geranylgeranyl diphosphate, which prenylates GTPases required for cytoskeletal organization and vesicular traffic in the osteoclast, leading to osteoclast inactivation [ 163 , 164 ].

Osteoporosis and statins

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to stimulate bone formation in laboratory studies, both in vitro and in vivo. Statin use in most, but not all observational studies is associated with a reduced risk of fracture, particularly hip fracture, even after adjustment for the confounding effects of age, weight and other medication use. This beneficial effect has not been observed in clinical trials designed to assess cardiovascular endpoints [ 165 ]. Men using statin drugs are more likely to have a greater BMD of the spine (p < 0.005), and men who receive statin drugs for more than 2 yr are approximately half as likely to develop osteoporosis. A similar effect is observed in women taking statins for any length of time [ 166 ]. Statin use in women is associated with a 3% greater adjusted BMD at the femoral neck, and BMD tends to be greater at the spine and whole body [ 167 ]. Nitrogen-containing bisphosphonate drugs inhibit the mevalonate pathway, preventing the production of isoprenoids, which consequently results in the inhibition of osteoclast formation and osteoclast function. Statins decrease the hepatic biosynthesis of cholesterol by blocking the mevalonate pathway, and can affect bone metabolism in vivo through effects on osteoclastic bone resorption. The ability of statin compounds to inhibit bone resorption is directly related to HMG-CoA reductase activity [ 168 ].

Osteoporosis, plant polyphenols, and fatty acids

Dietary supplementation with soybean isoflavone can prevent postmenopausal bone loss. In one study, postmenopausal women (n = 19), mean age 70.6 +/- 6.3 years and mean time since menopause 19.1 +/- 5.5 years, were given isoflavone supplements for 6 months. There was a 37% decrease in urinary concentrations of type 1 collagen alpha1-chain helical peptide (HP), a marker of bone resorption, during the isoflavone supplementation compared with baseline (p < 0.05) and a significant difference in mean (SE) HP excretion levels when isoflavone was compared with placebo (43.4 +/- 5.2 vs. 56.3 +/- 7.2 microg/mmol creatinine [cr], p < 0.05). With isoflavone supplementation, mean spine BMD at L2 and L3 was significantly greater when treatment was compared with control, with a difference between means of 0.03 +/- 0.04 g and 0.03 +/- 0.04 g (p < 0.05), respectively. There were nonsignificant increases from baseline for total spine BMC (3.5%), total spine BMD (1%), total hip BMC (3.6%), and total hip BMD (1.3%) with the isoflavone treatment [ 169 ]. Data from a randomized, double-blind, placebo-controlled, year long clinical trial has also suggested that supplementation with the dietary phytoestrogen genistein (54 mg/day) may be as effective as hormone replacement therapy in attenuating menopause-related bone loss [ 170 ].

Beneficial effects of omega 3 fatty acids on bone mineral density have been reported in rats and humans. In one study, sham and ovariectomized (OVX) mice were fed diets containing either 5% corn oil (CO), rich in omega-6 fatty acids or 5% fish oil (FO), rich in omega-3 fatty acids. Bone mineral density was analyzed by DXA. The serum lipid profile was analyzed by gas chromatography. Receptor activator of NF-kappaB ligand (RANKL) expression and cytokine production in activated T-cells were analyzed by flow cytometry and ELISA, respectively. Significantly increased bone mineral density loss (20% in distal left femur and 22.6% in lumbar vertebrae) was observed in OVX mice fed CO, whereas FO-fed mice showed only 10% and no change, respectively. Bone mineral density loss was correlated with increased RANKL expression in activated CD4+ T-cells from CO-fed OVX mice, but there was no change in FO-fed mice [ 171 ].

Aging, age-related disorders, and Interleukin 6

Evidence has linked IL-10 and IL-6 cytokine polymorphisms to longevity. Individuals who are genetically predisposed to produce high levels of IL-6 have a reduced capacity to reach the extreme limits of human life, whereas the high IL-10-producer genotype is increased among centenarians [ 172 ].

Telomere length is linked to age-associated diseases, with shorter telomeres in blood associated with an increased probability of mortality from infection or heart disease. In patients with multiple myeloma (MM), telomere length (TL) of MM cells is significantly shorter than that of the patients' own leukocytes. In one study, TL negatively correlated with age and with interleukin-6 (IL-6) and beta2-microglobulin levels [ 173 ]. Overproduction of IL-6, a pro-inflammatory cytokine, is associated with a spectrum of age-related conditions including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, certain cancers, periodontal disease, frailty, and functional decline. To describe the pattern of change in IL-6 over 6 years among older adults undergoing a chronic stressor, this longitudinal community study assessed the relationship between chronic stress and IL-6 production in 119 men and women who were caregiving for a spouse with dementia and 106 noncaregivers, with a mean age at study entry of 70.58 (SD = 8.03) for the full sample. On entry into this portion of the longitudinal study, 28 of the caregivers' spouses had already died, and an additional 50 of the 119 spouses died during the 6 years of this study. Levels of IL-6 and health behaviors associated with IL-6 were measured across 6 years. Caregivers' average rate of increase in IL-6 was about four times as large as that of noncaregivers. Moreover, the mean annual changes in IL-6 among former caregivers did not differ from that of current caregivers even several years after the death of the impaired spouse. There were no systematic group differences in chronic health problems, medications, or health-relevant behaviors that might have accounted for caregivers' steeper IL-6 slope. These data provide evidence of a key mechanism through which chronic stressors may accelerate risk of a host of age-related diseases by prematurely aging the immune response [ 174 ]. Interleukin-6 is also a causative factor in other manifestations of aging. Wrinkles on the skin are a manifestation of aging. Excess sunlight, smoking, and exposure to wind, heat, and harsh chemicals causes the outer layers of the skin to thicken and cause skin to wrinkle, sag and become leathery. Ultraviolet (UV) radiation from the sun is widely considered as a major cause of human skin photoaging and skin cancer. IL-6 is produced by keratinocytes in vivo and in vitro and the release is enhanced by UV light. A study was performed to investigate the effect of a single UV dose eliciting moderate to severe sunburn reaction on the production of IL-6 in vivo. Plasma of UV-treated human subjects was evaluated for IL-6 activity by testing its capacity to induce the proliferation of an IL-6-dependent hybridoma cell line (B9). In contrast to plasma samples obtained before UV exposure, post-UV-specimens contained significant levels of IL-6 peaking at 12 h after UV irradiation. Plasma IL-6 activity was neutralized by an antiserum directed against recombinant human IL-6 [ 175 ]. UV radiation-induced proinflammatory cytokines mediated by NF-kappaB reportedly play important roles in sunburn, skin damage, premature aging, and increases the risk of developing melanomas and other types of skin cancer. In one study, immunohistochemical and Western blot analysis and ELISA indicated that both nuclear p65 and secreted IL-6 were significantly (p < 0.05) induced by UVB (20, 30 mJ/cm2) and UVA irradiation (10, 20 J/cm2). NF-kappaB nuclear translocation and IL-6 secretion induced by UVB and UVA were dramatically inhibited by treatment of EGCG [ 176 ]. Higher levels of the systemic inflammatory markers CRP and IL-6 are independently associated with progression of age-related macular degeneration (AMD) [ 177 ].

Aging, age-related disorders, Interleukin-6 and gene therapy/modulation

Genetic polymorphisms involving a change of a single base, fromguanine to cytosine, at position – 174 in the 5' flankingregion of the interleukin-6 gene is of great importance becausethe G allele is associated with higher IL-6 production thanthe C allele. In vivo studies have found basal IL-6 levels to be twice ashigh in volunteers with the GG allele than in those with theCC allele. The polymorphism in the 5' flanking region, (an area important in theregulation of gene expression) alters the transcriptional response to stimuli such as LPS and IL-1 [ 178 ]. An increased frequency of an Xba I Restriction Fragment Length Polymorphism (RFLP, likelyto be due to 3' flanking region insertions, has been describedin some patients with SLE and elevated IL-6 levels [ 179 ]. Byusing polymerase chain reaction (PCR)-RFLP and sensitive polyacrylamide gel electrophoresis, an association between genotype for the 3' flanking region polymorphismand peak bone mineral density in women has been demonstrated [ 180 ]. Manipulating the genetic mechanismscontrolling the IL-6 levels and increasing the frequency of GG alleles in the population would prevent aging and age related diseases and be the key to eternal youth and immortality. Gene therapy will aim to provide for targeted gene transfer, controlled expression of the gene transferred and enhanced activity of the transferred gene product. An alternate means of gene therapy is gene modulation. In gene modulation, expression of an already expressed gene is increased by introducing exogenous normal genetic sequences and decreased by introducing antisense genes or gene fragments, or by introducing vectors that can produce ribozymes that can cleave specific mRNAs. Gene modulation can also be achieved by the introduction of exogenous normal genetic sequences that code for proteins that modulate the extent of gene expression, or affect the processing, assembly or secretion of gene products.

Conclusión

In conclusion, we have described the biochemical pathway from cholesterol synthesis to interleukin 6 mediated inflammation. Interleukin 6 mediated inflammation is the gatekeeper and common causative factor for aging and age-related disorders including Atherosclerosis, Peripheral Vascular Disease, Coronary Artery Disease, Osteoporosis, Type 2 Diabetes, Dementia and Alzheimer's disease and some forms of Arthritis and Cancer. We have clarified the relationship between some of these common illnesses and we determine that pleiotropic effects of bisphosphonates, statins and polyphenolic compounds are mediated by inhibition of Interleukin 6 mediated inflammation.

Isoprenoids, which are intermediates, generated in the cholesterol biosynthesis pathway, may play a role as significant as the end product cholesterol, in activation of Interleukin 6 mediated inflammation. Isoprenoids are generated by endogenous cellular cholesterol synthesis in the body as well as by cholesterol synthesis in activated monocytes during the inflammatory response. However, isoprenoids are but one component of the signaling pathway for Interleukin 6 mediated inflammation.

Inhibition of the signal transduction pathway for Interleukin 6 mediated inflammation is key to the prevention and treatment of aging and age-related disorders including atherosclerosis, peripheral vascular disease, coronary artery disease, osteoporosis, type 2 diabetes, dementia, Alzheimer's disease and some forms of arthritis and cancer. Inhibition of Interleukin 6 mediated inflammation may be achieved indirectly through regulation of endogenous cholesterol synthesis and isoprenoid depletion or by direct inhibition of the interleukin-6 signal transduction pathway.

Statins, Bisphosphonates and Polyphenolic Compounds have similar mechanisms of action and act on similar diseases in the following ways:

1. Statins and Bisphosphonates inhibit the Mevalonate to Cholesterol conversion pathway and cause isoprenoid depletion; with inhibition of interleukin-6 inflammation. Statins inhibit the enzyme HMG-CoA reductase and Bisphosphonates inhibit the enzyme FPP Synthase. Polyphenolic Compounds inhibit multiple pathways of signal transduction for Interleukin 6 mediated inflammation including inhibition of tyrosine kinase activity, inhibition of activation of NF-κB and inhibition of activation of IKK complex.

2. Statins, Bisphosphonates and Polyphenolic Compounds inhibit the JAK/STAT3 signaling pathway for Interleukin 6 mediated inflammation.

3. Statins, Bisphosphonates and Polyphenolic Compounds have common pleiotropic effects and decrease the progression of atherosclerotic vascular disease and inhibit bone resorption.

4. Combination treatment with agents that inhibit different aspects of the signal transduction pathways for interleukin 6 mediated inflammation, including Statins, Bisphosphonates and Polyphenolic Compounds, will be transformational and have better efficacy with fewer side effects in the prevention and treatment of aging and age-related disorders including atherosclerosis, peripheral vascular disease, coronary artery disease, osteoporosis, type 2 diabetes, dementia and some forms of arthritis and tumors. Evidence of safety and efficacy of combination treatment with inhibitors of Interleukin-6 mediated inflammation should be sought from new clinical trials.

Statins, Bisphosphonates are just indirect inhibitors of Interleukin-6 inflammation but yet both class of drugs have enabled a significant decrease in mortality and morbidity from these common illnesses.

Epidemiological evidence suggests that increased consumption of plant derived polyphenolic compounds is associated with decrease in mortality and morbidity from these common illnesses. Newer therapies will include delivering by gene therapy or gene modulation variations and/or modifications of the interleukin-6 gene associated with decreased or absent IL-6 production. Newer drugs will include interleukin-6 inhibitor/antibody, interleukin-6 receptor inhibitor/antibody, interleukin-6 antisense oligonucleotide (ASON), gp130 protein inhibitor/antibody, tyrosine kinases inhibitors/antibodies, serine/threonine kinases inhibitors/antibodies, mitogen-activated protein (MAP) kinase inhibitors/antibodies, phosphatidylinositol 3-kinase (PI3K) inhibitors/antibodies, Nuclear factor κB (NF-κB) inhibitors/antibodies, IκB kinase (IKK) inhibitors/antibodies, activator protein-1 (AP-1) inhibitors/antibodies, STAT transcription factors inhibitors/antibodies, altered IL-6, partial peptides of IL-6 or IL-6 receptor, or SOCS (suppressors of cytokine signaling) protein, PPAR gamma and/or PPAR beta/delta activators/ligands or a functional fragment thereof.

The public health significance of such new drugs and gene therapy will be transformational.