GALECTIN-3 INDUCES A DISTINCTIVE PATTERN OF CYTOKINE AND CHEMOKINE PRODUCTION IN RHEUMATOID SYNOVIAL FIBROBLASTS VIA SELECTIVE SIGNALLING PATHWAYS

ANDREW D. FILER; MAGDALENA BIK; GREG PARSONAGE; JOHN FITTON; EMILY TREBILCOCK; KATHERINE HOWLETT; KARIN RAZA; DAVID SIMONS; MIKE SALMON; DAGMAR SCHEEL TOELLNER; JANET M. LORD; GABRIEL A. RABINOVICH; CHRISTOPHER D. BUCKLEY

ARTHRITIS AND RHEUMATISM

Willey Interscience

Lugar: New York; Año: 2009 vol. 60 p. 1604 - 1614

0004-3591

Objective: High galectin-3 expression at sites of joint destruction in rheumatoid arthritis (RA) suggests a role in pathogenesis. Existing studies have demonstrated effects of galectins on immune cells such as lymphocytes and macrophages. We investigated the hypothesis that galectin-3 induces pro-inflammatory effects in RA by modulating the pattern of cytokine and chemokine production from synovial fibroblasts. arthritis (RA) suggests a role in pathogenesis. Existing studies have demonstrated effects of galectins on immune cells such as lymphocytes and macrophages. We investigated the hypothesis that galectin-3 induces pro-inflammatory effects in RA by modulating the pattern of cytokine and chemokine production from synovial fibroblasts. arthritis (RA) suggests a role in pathogenesis. Existing studies have demonstrated effects of galectins on immune cells such as lymphocytes and macrophages. We investigated the hypothesis that galectin-3 induces pro-inflammatory effects in RA by modulating the pattern of cytokine and chemokine production from synovial fibroblasts. arthritis (RA) suggests a role in pathogenesis. Existing studies have demonstrated effects of galectins on immune cells such as lymphocytes and macrophages. We investigated the hypothesis that galectin-3 induces pro-inflammatory effects in RA by modulating the pattern of cytokine and chemokine production from synovial fibroblasts. : High galectin-3 expression at sites of joint destruction in rheumatoid arthritis (RA) suggests a role in pathogenesis. Existing studies have demonstrated effects of galectins on immune cells such as lymphocytes and macrophages. We investigated the hypothesis that galectin-3 induces pro-inflammatory effects in RA by modulating the pattern of cytokine and chemokine production from synovial fibroblasts. Methods: Matched RA synovial and skin fibroblasts were pre-treated with galectin-3 or TNFá and levels of a panel of cytokines, chemokines and matrix metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. or TNFá and levels of a panel of cytokines, chemokines and matrix metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. or TNFá and levels of a panel of cytokines, chemokines and matrix metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. or TNFá and levels of a panel of cytokines, chemokines and matrix metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. Matched RA synovial and skin fibroblasts were pre-treated with galectin-3 or TNFá and levels of a panel of cytokines, chemokines and matrix metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. á and levels of a panel of cytokines, chemokines and matrix metalloproteinases determined using ELISA and multiplex assays. Specific inhibitors were used to dissect signalling pathways, confirmed by western blotting and NF-êB activation assay. activation assay. activation assay. activation assay. êB activation assay. Results: Galectin-3 induced secretion of IL-6, GM-CSF, CXCL8, and MMP-3 in both synovial and skin fibroblasts. By contrast, galectin-3 induced secretion of TNFá, CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. synovial and skin fibroblasts. By contrast, galectin-3 induced secretion of TNFá, CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. synovial and skin fibroblasts. By contrast, galectin-3 induced secretion of TNFá, CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. synovial and skin fibroblasts. By contrast, galectin-3 induced secretion of TNFá, CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. Galectin-3 induced secretion of IL-6, GM-CSF, CXCL8, and MMP-3 in both synovial and skin fibroblasts. By contrast, galectin-3 induced secretion of TNFá, CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. CCL2, CCL3 and CCL5 was significantly greater in synovial than skin fibroblasts. TNFá blockade ruled out autocrine TNFá stimulated induction of chemokines. The mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. activation was required for production of both IL-6 and CCL5. mitogen-activated protein kinases p38, JNK and ERK were necessary for IL-6 production, but PI3Kinase was required for selective CCL5 induction. NF-êB activation was required for production of both IL-6 and CCL5.