title: COX-2 inhibitors modulate IL-12 signaling through JAK-STAT pathway leading to Th1 response in experimental allergic encephalomyelitis.
abstract: Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated autoimmune disease model of multiple sclerosis (MS). IL-12 plays a crucial role in the pathogenesis of EAE/MS and inhibition of IL-12 production or IL-12 signaling was effective in preventing EAE. Cyclooxygenase (COX-2) is a key enzyme promoting inflammation in rheumatoid arthritis and tumor induced angiogenesis. Recent studies have shown that COX-2 inhibitors prevent EAE, however, their mechanism of action is not fully understood. In this study, we show that in vivo treatment (i.p.) with 100 mug COX-2 selective inhibitors (LM01, LM08, LM11, and NS398), on every other day from day 0 to 30, significantly reduced the incidence and severity of EAE in SJL/J and C57BL/6 mice. Further analyses showed that the COX-2 inhibitors reduced neural antigen-induced IL-12 production, T cell proliferation and Th1 differentiation ex vivo and in vitro. The COX-2 inhibitors also decreased IL-12-induced T cell responses through blocking tyrosine phosphorylation of JAK2, TYK2, STAT3, and STAT4 proteins in T cells. These results demonstrate that COX-2 inhibitors ameliorate EAE in association with the modulation of IL-12 signaling through JAK-STAT pathway leading to Th1 differentiation and suggest their use in the treatment of MS and other Th1 cell-mediated autoimmune diseases.
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Gladson
authors.initials: G
authors.lastname: Muthian
authors.forename: Himanshu P
authors.initials: HP
authors.lastname: Raikwar
authors.forename: Caroline
authors.initials: C
authors.lastname: Johnson
authors.forename: Johnson
authors.initials: J
authors.lastname: Rajasingh
authors.forename: Amit
authors.initials: A
authors.lastname: Kalgutkar
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
authors.forename: John J
authors.initials: JJ
authors.lastname: Bright
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D003711:Demyelinating Diseases / Q000188:drug therapy; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000502:physiology*; D053614:Janus Kinase 2; D051379:Mice; D008810:Mice, Inbred C57BL; D020528:Multiple Sclerosis, Chronic Progressive / Q000188:drug therapy; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000502:physiology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2