Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 14, Pages 5954-5959Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0812782106
Keywords
antigen-induced arthritis; chemokines; cytokines; rheumatoid arthritis; Th17
Categories
Funding
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo
- Pronex
- Fundacao de Amparo a Pesquisa do Estado do Amazonas
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (Brazil)
- The Wellcome Trust
- Medical Research Council (United Kingdom)
- MRC [G9818261, G0801198] Funding Source: UKRI
- Medical Research Council [G9818261, G0801198] Funding Source: researchfish
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IL-23/IL-17-induced neutrophil recruitment plays a pivotal role in rheumatoid arthritis (RA). However, the mechanism of the neutrophil recruitment is obscure. Here we report that prostaglandin enhances the IL-23/IL-17-induced neutrophil migration in a murine model of RA by inhibiting IL-12 and IFN gamma production. Methylated BSA (mBSA) and IL-23-induced neutrophil migration was inhibited by anti-IL-23 and anti-IL-17 antibodies, COX inhibitors, IL-12, or IFN gamma but was enhanced by prostaglandin E-2 (PGE(2)). IL-23-induced IL-17 production was increased by PGE(2) and suppressed by COX-inhibition or IL-12. Furthermore, COX inhibition failed to reduce IL-23-induced neutrophil migration in IL-12- or IFN gamma-deficient mice. IL-17-induced neutrophil migration was not affected by COX inhibitors, IL-12, or IFN gamma but was inhibited by MK886 (a leukotriene synthesis inhibitor), anti-TNF alpha, anti-CXCL1, and anti-CXCL5 antibodies and by repertaxin (a CXCR1/2 antagonist). These treatments all inhibited mBSA- or IL-23-induced neutrophil migration. IL-17 induced neutrophil chemotaxis through a CXC chemokines-dependent pathway. Our results suggest that prostaglandin plays an important role in IL-23-induced neutrophil migration in arthritis by enhancing IL-17 synthesis and by inhibiting IL-12 and IFN gamma production. We thus provide a mechanism for the pathogenic role of the IL-23/IL-17 axis in RA and also suggest an additional mechanism of action for nonsteroidal anti-inflammatory drugs.
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