title: IL-17 mediates articular hypernociception in antigen-induced arthritis in mice.
abstract: IL-17 is an important cytokine in the physiopathology of rheumatoid arthritis (RA). However, its participation in the genesis of nociception during RA remains undetermined. In this study, we evaluated the role of IL-17 in the genesis of articular nociception in a model of antigen (mBSA)-induced arthritis. We found that mBSA challenge in the femur-tibial joint of immunized mice induced a dose- and time-dependent mechanical hypernociception. The local IL-17 concentration within the mBSA-injected joints increased significantly over time. Moreover, co-treatment of mBSA challenged mice with an antibody against IL-17 inhibited hypernociception and neutrophil recruitment. In agreement, intraarticular injection of IL-17 induced hypernociception and neutrophil migration, which were reduced by the pre-treatment with fucoidin, a leukocyte adhesion inhibitor. The hypernociceptive effect of IL-17 was also reduced in TNFR1(-/-) mice and by pre-treatment with infliximab (anti-TNF antibody), a CXCR1/2 antagonist or by an IL-1 receptor antagonist. Consistent with these findings, we found that IL-17 injection into joints increased the production of TNF-alpha, IL-1beta and CXCL1/KC. Treatment with doxycycline (non-specific MMPs inhibitor), bosentan (ET(A)/ET(B) antagonist), indomethacin (COX inhibitor) or guanethidine (sympathetic blocker) inhibited IL-17-induced hypernociception. IL-17 injection also increased PGE(2) production, MMP-9 activity and COX-2, MMP-9 and PPET-1 mRNA expression in synovial membrane. These results suggest that IL-17 is a novel pro-nociceptive cytokine in mBSA-induced arthritis, whose effect depends on both neutrophil migration and various pro-inflammatory mediators, as TNF-alpha, IL-1beta, CXCR1/2 chemokines ligands, MMPs, endothelins, prostaglandins and sympathetic amines. Therefore, it is reasonable to propose IL-17 targeting therapies to control this important RA symptom.
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil Laboratory of Pharmacology, National Institute for Research in the Amazon (INPA), Manaus, Brazil Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Brazil.
authors.forename: Larissa G
authors.initials: LG
authors.lastname: Pinto
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.forename: Silvio M
authors.initials: SM
authors.lastname: Vieira
authors.forename: Henrique P
authors.initials: HP
authors.lastname: Lemos
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Ferreira
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000941:Antigens; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001168:Arthritis / Q000139:chemically induced / Q000150:complications* / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D016232:Endothelins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology* / Q000517:prevention & control; D000069285:Infliximab; D020381:Interleukin-17 / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D017288:Pain Threshold / Q000187:drug effects*; D011134:Polysaccharides / Q000627:therapeutic use; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency; D012709:Serum Albumin; D015054:Zymosan
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D018501:Antirheumatic Agents; D016207:Cytokines; D016232:Endothelins; D004791:Enzyme Inhibitors; D020381:Interleukin-17; D011134:Polysaccharides; D047888:Receptors, Tumor Necrosis Factor, Type I; D012709:Serum Albumin; C506236:Tnfrsf1a protein, mouse; D015054:Zymosan; C007789:fucoidan; D000069285:Infliximab; D015232:Dinoprostone