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: Larissa G Pinto, Thiago M Cunha, Silvio M Vieira, Henrique P Lemos, Waldiceu A Verri Jr, Fernando Q Cunha, Sergio H Ferreira
• Journal: Pain (Pain) Vol. 148 Issue 2 Pg. 247-256 (Feb 2010) ISSN: 1872-6623 [Electronic] United States
• PMID: 19969421 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antigens
• Antirheumatic Agents
• Cytokines
• Endothelins
• Enzyme Inhibitors
• Interleukin-17
• Polysaccharides
• Receptors, Tumor Necrosis Factor, Type I
• Serum Albumin
• Tnfrsf1a protein, mouse
• Zymosan
• fucoidan
• Infliximab
• Dinoprostone

Topics

• Analysis of Variance
• Animals
• Antibodies, Monoclonal (therapeutic use)
• Antigens
• Antirheumatic Agents (therapeutic use)
• Arthritis (chemically induced, complications, immunology)
• Cell Movement (drug effects)
• Cytokines (metabolism)
• Dinoprostone (metabolism)
• Disease Models, Animal
• Endothelins (metabolism)
• Enzyme Inhibitors (therapeutic use)
• Gene Expression Regulation (drug effects)
• Hyperalgesia (drug therapy, etiology, prevention & control)
• Infliximab
• Interleukin-17 (therapeutic use)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Neutrophils (drug effects, physiology)
• Pain Threshold (drug effects)
• Polysaccharides (therapeutic use)
• Receptors, Tumor Necrosis Factor, Type I (deficiency)
• Serum Albumin
• Zymosan