title: 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.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo 14.049-900, Brazil.
authors.forename: Henrique P
authors.initials: HP
authors.lastname: Lemos
authors.forename: Renata
authors.initials: R
authors.lastname: Grespan
authors.forename: Silvio M
authors.initials: SM
authors.lastname: Vieira
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
authors.forename: Karla S S
authors.initials: KS
authors.lastname: Fernandes
authors.forename: Fabricio O
authors.initials: FO
authors.lastname: Souto
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Ferreira
authors.forename: Foo Y
authors.initials: FY
authors.lastname: Liew
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology*; D053759:Interleukin-23 / Q000276:immunology*; D051379:Mice; D020556:Neutrophil Infiltration / Q000276:immunology*; D011453:Prostaglandins / Q000502:physiology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D020381:Interleukin-17; D053759:Interleukin-23; D011453:Prostaglandins; D018664:Interleukin-12; D007371:Interferon-gamma; D015232:Dinoprostone