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Papel novedoso de la PKR en la activación del inflamatoma y la liberación de HMGB1
Ben Lu1, Takahisa Nakamura, Karen Inouye
1Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, New York 11030, USA. blu@nshs.edu
Nature
|July 18, 2012
Resumen
La proteína quinasa dependiente de ARN de doble cadena (PKR) es crucial para la activación del inflamatorio. La inhibición de la PKR puede potencialmente tratar enfermedades inflamatorias mediante el bloqueo de la liberación de citoquinas.
Área de la Ciencia:
- Inmunología Inmunología.
- Biología Molecular Biología Molecular
- La señalización celular.
Sus antecedentes:
- El complejo inflamatorio orquesta la liberación de citoquinas inflamatorias clave, incluidas IL-1β, IL-18 y HMGB1.
- Comprender los mecanismos que regulan la activación del inflamatorio es fundamental para desarrollar terapias antiinflamatorias dirigidas.
Objetivo del estudio:
- Investigar el papel de la proteína quinasa dependiente de ARN de doble cadena (PKR, también conocida como EIF2AK2) en la activación del inflamatorio.
- Para dilucidar los mecanismos moleculares por los cuales PKR influye en la señalización inflamatoria.
Principales métodos:
- Estimulación de los macrófagos con varios agonistas del inflamatorio.
- La deleción genética y la inhibición farmacológica de la PKR.
- Evaluación de la liberación de citoquinas (IL-1β, IL-18, HMGB1).
- Pruebas de coinmunoprecipitación para estudiar las interacciones de las proteínas.
- Reconstitución in vitro de la actividad del inflamasoma utilizando proteínas recombinantes.
Principales resultados:
- La autofosforilación de la PKR fue inducida tras la exposición a agonistas inflamatorios.
- La deficiencia o inhibición de la PKR deterioró significativamente la activación del inflamatorio en diversos estímulos, incluidos los componentes bacterianos y virales, el ATP y las sustancias cristalinas.
- La PKR interactúa físicamente con varios componentes del inflamatorio (NLRP3, NLRP1, NLRC4, AIM2).
- La reconstrucción de la actividad inflamatoria se logró utilizando PKR, NLRP3, ASC y pro-caspase-1 en un sistema libre de células.
Conclusiones:
- La PKR juega un papel fundamental y amplio en la regulación de la activación del inflamatorio.
- La PKR representa un objetivo terapéutico potencial para el manejo de condiciones inflamatorias.
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