p38 alpha MAP Kinase Controls IL-17 Synthesis in Vogt-Koyanagi-Harada Syndrome and Experimental Autoimmune Uveitis

p38 alpha MAP Kinase Controls IL-17 Synthesis in Vogt-Koyanagi-Harada Syndrome and Experimental Autoimmune Uveitis

Author Commodaro, Alessandra Goncalves Autor UNIFESP Google Scholar
Bombardieri, Cintia Raquel Google Scholar
Schatzmann Peron, Jean Pierre Google Scholar
Saito, Kelly Cristina Google Scholar
Guedes, Pedro Mancini Google Scholar
Hamassaki, Dania E. Google Scholar
Belfort, Rubens Neto Autor UNIFESP Google Scholar
Rizzo, Luiz Vicente Google Scholar
Belfort, Rubens Junior Autor UNIFESP Google Scholar
Camargo, Maristela Martins de Google Scholar
Institution Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Albert Einstein Jewish Inst Educ & Res
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 p38 alpha 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 p38 alpha MAPK inhibitor and then assayed for IL-17, IFN-gamma, and IL-4 production.RESULTS. the inhibition of p38 alpha 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 p38 alpha MAPK-MSK1/2 is involved in the control of IL-17 synthesis by CD4(+) T cells and that inhibition of p38 alpha MAPK in vitro suppresses IL-17 synthesis but that inhibition of this kinase in vivo did not protect from EAU. (Invest Ophthalmol Vis Sci. 2010;51:3567-3574) DOI: 10.1167/iovs.09-4393
Language English
Sponsor São Paulo State Science Council
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Grant number São Paulo State Science Council: 01/02584-2
CAPES: PNPD 0188085
Date 2010-07-01
Published in Investigative Ophthalmology & Visual Science. Rockville: Assoc Research Vision Ophthalmology Inc, v. 51, n. 7, p. 3567-3574, 2010.
ISSN 0146-0404 (Sherpa/Romeo, impact factor)
Publisher Assoc Research Vision Ophthalmology Inc
Extent 3567-3574
Origin http://dx.doi.org/10.1167/iovs.09-4393
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000279047500034
URI http://repositorio.unifesp.br/handle/11600/32653

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