p38{alpha} MAP kinase controls IL-17 synthesis in vogt-koyanagi-harada syndrome and experimental autoimmune uveitis.
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.
Commodaro
Alessandra Gonçalves
AG
Vision Institute, Federal University of São Paulo, São Paulo, Brazil.
Bombardieri
Cíntia Raquel
CR
Peron
Jean Pierre Schatzmann
JP
Saito
Kelly Cristina
KC
Guedes
Pedro Mancini
PM
Hamassaki
Dânia E
DE
Belfort
Rubens N
RN
Rizzo
Luiz Vicente
LV
Belfort
Rubens
R
de Camargo
Maristela Martins
MM
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
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