Aberrant ROCK activation promotes the development of type I diabetes in NOD mice.
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.
Department of Medicine, Columbia University, NY 10032, USA.
Partha S
PS
Biswas
Sanjay
S
Gupta
Emily
E
Chang
Govind
G
Bhagat
Alessandra B
AB
Pernis
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology; D005260:Female; D050835:Interferon Regulatory Factors / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000032:analysis / Q000276:immunology; D007378:Interleukins / Q000032:analysis / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000098546:Interleukin-21; D000099218:Interferon Regulatory Factor-4
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D050835:Interferon Regulatory Factors; D020381:Interleukin-17; D007378:Interleukins; D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases; D000098546:Interleukin-21; D000099218:Interferon Regulatory Factor-4; C515855:Rock2 protein, mouse; C049347:fasudil