Abstract
CD4(+) T helper (Th) cells differentiate into distinct effector subsets that are critical for host defense, but are also implicated in the pathogenesis of autoimmune disorders. Thelper17 (Th17) cells in particular are emerging as important drivers of multiple diseases including psoriasis, spondyloarthropathy and multiple sclerosis. To gain insight into the function of Th17 cells, we performed transcriptional profiling in hopes of elucidating products not previously recognized as being functionally relevant in these T cells. Herein, we demonstrate that tissue inhibitor of metalloproteinase 1 (TIMP1), a secreted protein with pleiotropic effects on cellular growth, survival and integrity of the extracellular matrix, is preferentially produced by Th17 and Th1 cells. We further show that Th1 and Th17 cell TIMP1 regulation follows separate mechanisms with a requirement for STAT4 in the former and STAT3 in the latter. Finally, we demonstrate that when restricted to T cells, expression of TIMP1 promotes neuropathology in experimental allergic encephalomyelitis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cytokines / genetics
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Cytokines / immunology
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Encephalomyelitis, Autoimmune, Experimental / genetics*
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Encephalomyelitis, Autoimmune, Experimental / physiopathology
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Gene Expression Profiling
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Gene Expression Regulation
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Humans
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Mice
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Mice, Transgenic
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Organ Specificity
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / immunology*
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STAT4 Transcription Factor / genetics
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STAT4 Transcription Factor / immunology*
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Signal Transduction
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Spleen / immunology
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Spleen / pathology
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Th1 Cells / immunology*
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Th1 Cells / pathology
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Th17 Cells / immunology*
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Th17 Cells / pathology
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Tissue Inhibitor of Metalloproteinase-1 / genetics
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Tissue Inhibitor of Metalloproteinase-1 / immunology*
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Transcription, Genetic
Substances
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Cytokines
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STAT3 Transcription Factor
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STAT4 Transcription Factor
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Stat3 protein, mouse
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Stat4 protein, mouse
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Timp1 protein, mouse
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Tissue Inhibitor of Metalloproteinase-1