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PMID: 19289819 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibiting IL-12 and IFNgamma production.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 106 ·No. 14 ·2009-04-07 ·Pages 5954-9

Lemos HP, Grespan R, Vieira SM, Cunha TM, Verri WA, Fernandes KS, Souto FO, McInnes IB, Ferreira SH, Liew FY, Cunha FQ

Abstract

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 IFNgamma 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 IFNgamma-deficient mice. IL-17-induced neutrophil migration was not affected by COX inhibitors, IL-12, or IFNgamma but was inhibited by MK886 (a leukotriene synthesis inhibitor), anti-TNFalpha, 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 IFNgamma 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.

MeSH Terms
Animals Arthritis, Rheumatoid/pathology Cyclooxygenase Inhibitors/pharmacology Dinoprostone/pharmacology Inflammation/metabolism Interferon-gamma/antagonists & inhibitors Interleukin-12/antagonists & inhibitors Interleukin-17/biosynthesis,immunology Interleukin-23/immunology Mice Neutrophil Infiltration/immunology Prostaglandins/physiology
Chemicals
Cyclooxygenase Inhibitors Interleukin-17 Interleukin-23 Prostaglandins Interleukin-12 Interferon-gamma Dinoprostone
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Lemos Henrique P
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo 14.049-900, Brazil.
Grespan Renata
Vieira Silvio M
Cunha Thiago M
Verri Waldiceu A
Fernandes Karla S S
Souto Fabricio O
McInnes Iain B
Ferreira Sergio H
Liew Foo Y
Cunha Fernando Q
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0812782106
Published
2009-04-07
Epub
2009-00-16
Pages
5954-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2667068
Subset
IM
Grants
Medical Research Council · G0801198 · United Kingdom
Medical Research Council · G9818261 · United Kingdom
External Links
PubMed source DOI: 10.1073/pnas.0812782106 PMC Full Text View journal details
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