Aberrant ROCK activation promotes the development of type I diabetes in NOD mice

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• 作者：Partha S. Biswas ; Sanjay Gupta ; Emily Chang ; Govind Bhagat ; Aless ; ra B. Pernis
• 关键词：Type 1 diabetes ; IL-21 ; IL-17 ; Signaling pathways
• 刊名：Cellular Immunology
• 出版年：2011
• 出版时间：2011
• 年：2011
• 卷：266
• 期：2
• 页码：111-115
• 全文大小：641 K

文摘

Aberrant production of IL-21 by T cells is critical for the development of type 1 diabetes (T1D) in NOD mice. The pathogenic effects of IL-21 are partly due to its ability to promote the generation of T_H-17 cells. Interferon Regulatory Factor (IRF4) is a crucial regulator of IL-17 and IL-21 production. We recently found that the serine-threonine kinase ROCK2 phosphorylates IRF4 and regulates its ability to control IL-17 and IL-21 production. Here we show that NOD T cells aberrantly activate ROCK2. We furthermore demonstrate that ROCK inhibition corrects the abnormal IRF4 function in NOD T cells and diminishes their production of IL-17 and IL-21. Importantly, administration of a ROCK inhibitor to NOD mice protects against diabetes development. These studies thus support the idea that ROCK2 is inappropriately activated in NOD T cells and that ROCK kinases could represent important therapeutic targets for the treatment of T1D.