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

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.

• Authors: Henrique P Lemos, Renata Grespan, Silvio M Vieira, Thiago M Cunha, Waldiceu A Verri Jr, Karla S S Fernandes, Fabricio O Souto, Iain B McInnes, Sergio H Ferreira, Foo Y Liew, Fernando Q Cunha
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 14 Pg. 5954-9 (Apr 07 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19289819 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclooxygenase Inhibitors
• Interleukin-17
• Interleukin-23
• Prostaglandins
• Interleukin-12
• Interferon-gamma
• Dinoprostone

Topics

• 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)