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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
9
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pubmed:dateCreated |
2010-9-2
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pubmed:abstractText |
Deregulated production of IL-17 and IL-21 plays a key pathogenic role in many autoimmune disorders. A delineation of the mechanisms that underlie the inappropriate synthesis of IL-17 and IL-21 in autoimmune diseases can thus provide important insights into potential therapies for these disorders. Here we have shown that the serine-threonine kinase Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) becomes activated in mouse T cells under Th17 skewing conditions and phosphorylates interferon regulatory factor 4 (IRF4), a transcription factor that is absolutely required for the production of IL-17 and IL-21. We furthermore demonstrated that ROCK2-mediated phosphorylation of IRF4 regulated the synthesis of IL-17 and IL-21 and the differentiation of Th17 cells. Whereas CD4+ T cells from WT mice activated ROCK2 physiologically under Th17 conditions, CD4+ T cells from 2 different mouse models of spontaneous autoimmunity aberrantly activated ROCK2 under neutral conditions. Moreover, administration of ROCK inhibitors ameliorated the deregulated production of IL-17 and IL-21 and the inflammatory and autoantibody responses observed in these autoimmune mice. Our findings thus uncover a crucial link among ROCK2, IRF4, and the production of IL-17 and IL-21 and support the idea that selective inhibition of ROCK2 could represent an important therapeutic regimen for the treatment of autoimmune disorders.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
1558-8238
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
1
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pubmed:volume |
120
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3280-95
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pubmed:dateRevised |
2011-10-11
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pubmed:meshHeading |
pubmed-meshheading:20697158-Animals,
pubmed-meshheading:20697158-Autoimmunity,
pubmed-meshheading:20697158-Cell Differentiation,
pubmed-meshheading:20697158-Interferon Regulatory Factors,
pubmed-meshheading:20697158-Interleukin-17,
pubmed-meshheading:20697158-Interleukins,
pubmed-meshheading:20697158-Mice,
pubmed-meshheading:20697158-Mice, Inbred BALB C,
pubmed-meshheading:20697158-Mice, Inbred C57BL,
pubmed-meshheading:20697158-Mice, Knockout,
pubmed-meshheading:20697158-Mice, Transgenic,
pubmed-meshheading:20697158-Phosphorylation,
pubmed-meshheading:20697158-Protein-Serine-Threonine Kinases,
pubmed-meshheading:20697158-T-Lymphocytes,
pubmed-meshheading:20697158-rho-Associated Kinases
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pubmed:year |
2010
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pubmed:articleTitle |
Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice.
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pubmed:affiliation |
Department of Medicine, Columbia University, New York, New York, USA.
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pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Extramural
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