IL-17 mediates articular hypernociception in antigen-induced arthritis in mice

Pain. 2010 Feb;148(2):247-56. doi: 10.1016/j.pain.2009.11.006. Epub 2009 Dec 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Antibodies, Monoclonal / therapeutic use
  • Antigens*
  • Antirheumatic Agents / therapeutic use
  • Arthritis / chemically induced
  • Arthritis / complications*
  • Arthritis / 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*
  • Hyperalgesia / etiology*
  • Hyperalgesia / prevention & control
  • Infliximab
  • Interleukin-17 / therapeutic use*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / drug effects
  • Neutrophils / physiology
  • Pain Threshold / drug effects*
  • Polysaccharides / therapeutic use
  • Receptors, Tumor Necrosis Factor, Type I / deficiency
  • Serum Albumin
  • Zymosan

Substances

  • 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