Interleukin-20 antibody is a potential therapeutic agent for experimental arthritis

Arthritis Rheum. 2010 Nov;62(11):3311-21. doi: 10.1002/art.27689.

Abstract

Objective: Interleukin-20 (IL-20) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA). We investigated whether anti-IL-20 antibody treatment would modulate the severity of the disease in a collagen-induced arthritis (CIA) rat model.

Methods: We generated a CIA model by immunizing rats with bovine type II collagen. Rats with CIA were treated subcutaneously with anti-IL-20 antibody 7E, with the tumor necrosis factor (TNF) blocker etanercept, or with 7E in combination with etanercept. Arthritis severity was determined according to the hind paw thickness, arthritis severity score, degree of cartilage damage, bone mineral density, and cytokine production, which were evaluated using radiologic scans, microfocal computed tomography, and enzyme-linked immunosorbent assay. To analyze gene regulation by IL-20, rat synovial fibroblasts (SFs) were isolated and analyzed for the expression of RANKL, IL-17, and TNFα. We also used real-time quantitative polymerase chain reaction analysis and flow cytometry to determine IL-20-regulated RANKL in mouse osteoblastic MC3T3-E1 cells and Th17 cells.

Results: In vivo, treatment with 7E alone or in combination with etanercept significantly reduced the severity of arthritis by decreasing the hind paw thickness and swelling, preventing cartilage damage and bone loss, and reducing the expression of IL-20, IL-1β, IL-6, RANKL, and matrix metalloproteinases (MMPs) in synovial tissue. In vitro, IL-20 induced TNFα expression in SFs from rats with CIA. IL-20 markedly induced RANKL production in SFs, osteoblasts, and Th17 cells.

Conclusion: Selectively blocking IL-20 inhibited inflammation and bone loss in rats with CIA. Treatment with 7E combined with etanercept protected rats from CIA better than treatment with etanercept alone. Our findings provide evidence that IL-20 is a novel target and that 7E may be a potential therapeutic agent for RA.

MeSH terms

  • Analysis of Variance
  • Animals
  • Antibodies / therapeutic use*
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / therapy*
  • Cell Line
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Etanercept
  • Fibroblasts / metabolism
  • Flow Cytometry
  • Immunoglobulin G / therapeutic use*
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism
  • Interleukins / antagonists & inhibitors*
  • Interleukins / immunology
  • Matrix Metalloproteinases / genetics
  • Matrix Metalloproteinases / metabolism
  • Mice
  • Osteoblasts / metabolism
  • RANK Ligand / genetics
  • RANK Ligand / metabolism
  • Rats
  • Receptors, Tumor Necrosis Factor / therapeutic use*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Severity of Illness Index
  • Synovial Membrane / metabolism

Substances

  • Antibodies
  • Immunoglobulin G
  • Interleukin-17
  • Interleukins
  • RANK Ligand
  • Receptors, Tumor Necrosis Factor
  • Matrix Metalloproteinases
  • Etanercept
  • interleukin 20