Pathogenic role of the CXCL16-CXCR6 pathway in rheumatoid arthritis

Arthritis Rheum. 2005 Oct;52(10):3004-14. doi: 10.1002/art.21301.


Objective: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with massive T cell infiltration into the synovium. The accumulated T cells express type 1 cytokines, such as interferon-gamma (IFNgamma) and tumor necrosis factor alpha, and activated markers of inflammation, such as CD154 and inducible costimulator (ICOS). It is thought that chemokines contribute to T cell accumulation in the synovium. In this study, we examined the role of CXCL16 and CXCR6 in T cell migration and stimulation in RA synovium.

Methods: Expression of CXCL16 and CXCR6 was analyzed by immunohistochemistry, reverse transcription-polymerase chain reaction, Western blotting, and/or flow cytometry. Migration activity was assessed using a chemotaxis chamber. IFNgamma production was analyzed by enzyme-linked immunosorbent assay. The effect of anti-CXCL16 monoclonal antibody on murine collagen-induced arthritis (CIA) was evaluated.

Results: CXCL16 was expressed in RA synovium. CXCR6 was expressed more frequently on synovial T cells than in peripheral blood. Moreover, CXCR6-positive synovial T cells more frequently expressed CD154 and ICOS than did CXCR6-negative T cells. Stimulation with interleukin-15 (IL-15) up-regulated the expression of CXCR6 on peripheral blood T cells, and then stimulation with CXCL16 induced migration of IL-15-stimulated T cells and enhanced IFNgamma production. Furthermore, anti-CXCL16 monoclonal antibody significantly reduced the clinical arthritis score and reduced infiltration of inflammatory cells and bone destruction in the synovium of mice with CIA.

Conclusion: Our results indicate that CXCL16 plays an important role in T cell accumulation and stimulation in RA synovium and suggest that CXCL16 could be a target molecule in new therapies for RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Arthritis, Rheumatoid / etiology
  • Arthritis, Rheumatoid / immunology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Chemokine CXCL16
  • Chemokine CXCL6
  • Chemokines, CXC / immunology*
  • Chemokines, CXC / metabolism
  • Female
  • Humans
  • Male
  • Membrane Proteins / immunology*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred DBA
  • Middle Aged
  • Receptors, CXCR6
  • Receptors, Chemokine
  • Receptors, Cytokine / immunology*
  • Receptors, Cytokine / metabolism
  • Receptors, G-Protein-Coupled / immunology*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Immunologic / immunology*
  • Receptors, Immunologic / metabolism
  • Receptors, Scavenger
  • Receptors, Virus / immunology*
  • Receptors, Virus / metabolism
  • Synovial Membrane / cytology
  • Synovial Membrane / immunology


  • Antibodies, Monoclonal
  • CXCL16 protein, human
  • CXCR6 protein, human
  • Chemokine CXCL16
  • Chemokine CXCL6
  • Chemokines, CXC
  • Cxcl16 protein, mouse
  • Membrane Proteins
  • Receptors, CXCR6
  • Receptors, Chemokine
  • Receptors, Cytokine
  • Receptors, G-Protein-Coupled
  • Receptors, Immunologic
  • Receptors, Scavenger
  • Receptors, Virus