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Cell Immunol. 2011;266(2):111-5. doi: 10.1016/j.cellimm.2010.10.009. Epub 2010 Nov 6.

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

Author information

1
Department of Medicine, Columbia University, NY 10032, USA.

Abstract

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.

PMID:
21111405
PMCID:
PMC3031108
DOI:
10.1016/j.cellimm.2010.10.009
[Indexed for MEDLINE]
Free PMC Article

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