Open AccessGalectin 3 induces a distinctive pattern of cytokine and chemokine production in rheumatoid synovial fibroblasts via selective signaling pathways
Author(s) -
Filer Andrew,
Bik Magdalena,
Parsonage Greg N.,
Fitton John,
Trebilcock Emily,
Howlett Katherine,
Cook Michelle,
Raza Karim,
Simmons David L.,
Thomas Andrew M. C.,
Salmon Mike,
ScheelToellner Dagmar,
Lord Janet M.,
Rabinovich Gabriel A.,
Buckley Christopher D.
Publication year - 2009
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.24574
Subject(s) - chemokine , proinflammatory cytokine , ccl5 , cytokine , tumor necrosis factor alpha , autocrine signalling , ccl3 , ccl2 , cancer research , synovial membrane , immunology , microbiology and biotechnology , inflammation , biology , medicine , immune system , t cell , receptor , il 2 receptor
Objective High expression of galectin 3 at sites of joint destruction in rheumatoid arthritis (RA) suggests that galectin 3 plays a role in RA pathogenesis. Previous studies have demonstrated the effects of galectins on immune cells, such as lymphocytes and macrophages. This study was undertaken to investigate the hypothesis that galectin 3 induces proinflammatory effects in RA by modulating the pattern of cytokine and chemokine production in synovial fibroblasts. Methods Matched samples of RA synovial and skin fibroblasts were pretreated with galectin 3 or tumor necrosis factor α (TNFα), and the levels of a panel of cytokines, chemokines, and matrix metalloproteinases (MMPs) were determined using enzyme‐linked immunosorbent assays and multiplex assays. Specific inhibitors were used to dissect signaling pathways, which were confirmed by Western blotting and NF‐κB activation assay. Results Galectin 3 induced secretion of interleukin‐6 (IL‐6), granulocyte–macrophage colony‐stimulating factor, CXCL8, and MMP‐3 in both synovial and skin fibroblasts. By contrast, galectin 3–induced secretion of TNFα, CCL2, CCL3, and CCL5 was significantly greater in synovial fibroblasts than in skin fibroblasts. TNFα blockade ruled out autocrine TNFα‐stimulated induction of chemokines. The MAPKs p38, JNK, and ERK were necessary for IL‐6 production, but phosphatidylinositol 3‐kinase (PI 3‐kinase) was required for selective CCL5 induction. NF‐κB activation was required for production of both IL‐6 and CCL5. Conclusion Our findings indicate that galectin 3 promotes proinflammatory cytokine secretion by tissue fibroblasts. However, galectin 3 induces the production of mononuclear cell–recruiting chemokines uniquely from synovial fibroblasts, but not matched skin fibroblasts, via a PI 3‐kinase signaling pathway. These data provide further evidence of the role of synovial fibroblasts in regulating the pattern and persistence of the inflammatory infiltrate in RA and suggest a new and important functional consequence of the observed high expression of galectin 3 in the rheumatoid synovium.