title: p38{alpha} MAP kinase controls IL-17 synthesis in vogt-koyanagi-harada syndrome and experimental autoimmune uveitis.
abstract: PURPOSE. Interleukin (IL)-17, which is responsible for the initial influx of leukocytes into the target tissue, was recently described as the main cytokine involved in autoimmune diseases. Vogt-Koyanagi-Harada (VKH) syndrome is a significant cause of noninfectious blindness in the world. Herein the authors aimed at unraveling the involvement of IL-17 in VKH and in experimental autoimmune uveitis, focusing on the signaling pathways involved in IL-17 synthesis. METHODS. Mice were immunized with 161-180 peptide and pertussis toxin. Draining lymph node cells, harvested 21 days after immunization, were cultured in the presence or absence of p38alpha mitogen-activated protein kinase (MAPK) inhibitor (SB203580) and assayed for cytokine production and quantification of CD4(+)IL-17(+) cells. Mice received intraocular injections of SB203580, and disease severity was evaluated by histologic examination of the enucleated eyes at day 21. CD4(+) lymphocytes from MSK-1/2-deficient mice, human CD4(+) cells silenced with MSK1 siRNA, or peripheral blood mononuclear cells (PBMCs) from VKH patients were cultured in the presence or absence of p38alpha MAPK inhibitor and then assayed for IL-17, IFN-gamma, and IL-4 production. RESULTS. The inhibition of p38alpha MAPK fully blocked the synthesis of IL-17 by PBMCs from VKH patients and lymphocytes from EAU mice. The absence of the msk1/2 gene resulted in failure to produce IL-17 by murine and human lymphocytes. Interestingly, intraocular injections of SB203580 in EAU mice did not suppress development of the disease. CONCLUSIONS. These data show that p38alpha MAPK-MSK1/2 is involved in the control of IL-17 synthesis by CD4(+) T cells and that inhibition of p38alpha MAPK in vitro suppresses IL-17 synthesis but that inhibition of this kinase in vivo did not protect from EAU.
authors.affiliation: Vision Institute, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Alessandra Gonçalves
authors.initials: AG
authors.lastname: Commodaro
authors.forename: Cíntia Raquel
authors.initials: CR
authors.lastname: Bombardieri
authors.forename: Jean Pierre Schatzmann
authors.initials: JP
authors.lastname: Peron
authors.forename: Kelly Cristina
authors.initials: KC
authors.lastname: Saito
authors.forename: Pedro Mancini
authors.initials: PM
authors.lastname: Guedes
authors.forename: Dânia E
authors.initials: DE
authors.lastname: Hamassaki
authors.forename: Rubens N
authors.initials: RN
authors.lastname: Belfort
authors.forename: Luiz Vicente
authors.initials: LV
authors.lastname: Rizzo
authors.forename: Rubens
authors.initials: R
authors.lastname: Belfort
authors.forename: Maristela Martins
authors.initials: MM
authors.lastname: de Camargo
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001327:Autoimmune Diseases / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005312:Fetal Blood; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020381:Interleukin-17 / Q000096:biosynthesis*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008875:Middle Aged; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014605:Uveitis / Q000378:metabolism*; D014607:Uveomeningoencephalitic Syndrome / Q000378:metabolism*; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D020381:Interleukin-17; D011725:Pyridines; D034741:RNA, Small Interfering; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C485459:Rps6ka4 protein, mouse; C116919:mitogen and stress-activated protein kinase 1; D048308:Mitogen-Activated Protein Kinase 14; C093642:SB 203580