1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNgamma axis leading to Th1 response in experimental allergic encephalomyelitis.
Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated autoimmune disease model of multiple sclerosis (MS). Vitamin D deficiency is commonly observed in MS patients and vitamin D supplements reduce the clinical symptoms of EAE and MS. Earlier studies have shown that in vivo treatment with vitamin D analogs ameliorates EAE in association with the inhibition of IL-12 production and Th1 differentiation. The mechanisms in the regulation of Th1 response by vitamin D in EAE/MS are, however, not known. We show that in vivo treatment of C57BL/6 and SJL/J mice (i.p.) with 100 ng of 1,25 dihydroxyvitamin D3, on every other day from Day 0-30, ameliorates EAE in association with the inhibition of IL-12 production and neural antigen-specific Th1 response. In vitro treatment with 1,25(OH)2D3 inhibited IFNgamma-induced tyrosine phosphorylation of STAT1, without affecting JAK2, in EOC-20 microglial cells. Treatment of activated T cells with 1,25(OH)2D3 also inhibited the IL-12-induced tyrosine phosphorylation of JAK2, TYK2, STAT3, and STAT4 in association with a decrease in T cell proliferation in vitro. These findings highlight the fact that vitamin D modulates JAK-STAT signaling pathway in IL-12/IFNgamma axis leading to Th1 differentiation and further suggest its use in the treatment of MS and other Th1 cell-mediated autoimmune diseases.
Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Gladson
G
Muthian
Himanshu P
HP
Raikwar
Johnson
J
Rajasingh
John J
JJ
Bright
D000818:Animals; D002117:Calcitriol / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism*; D053614:Janus Kinase 2; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D018664:Interleukin-12; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D002117:Calcitriol