Objectives: In synovial tissues of rheumatoid arthritis (RA) patients strong expression of laminins and integrins co-localizes with elevated expression of inflammatory cytokines. Synovial fibroblasts (SF) contribute to the pathogenesis of RA through elevated expression of cytokines and chemoattractant factors, one of which is IL-16. We therefore investigated regulatory pathways of IL-16 in SF from RA and osteoarthritis (OA) patients.
Methods: SF were seeded in laminin-coated flasks and activated by the addition of cytokines. Expression of IL-16 was investigated by quantitative RT-PCR, immunoblotting, and ELISA; its biological activity was determined by a cell migration assay. Cell - matrix interactions were investigated by cell binding and attachment assays. Relevant intracellular signaling pathways were studied by immunoblotting and with pharmacological blocking reagents.
Results: The stimulation of SF with TGF-β1 and growth on laminin-111 (LM-111) significantly increased the expression of IL-16. In RA-SF, binding to LM-111 induced significantly more IL-16 mRNA than in OA-SF (p<0.05). The IL-16 cytokine was detected in supernatants of TGF-β1-activated and in LM-111 plus TGF-β1-activated RA-SF (38 to 62 pg/ml), but not in supernatants of OA-SF. This IL-16 regulation involved p38MAPK, ERK1/2 and SMAD2 signaling, but not NFκB.
Conclusions: Binding of RA-SF to LM-111 in the presence of TGF-β1 triggers a significant IL-16 response and thus may contribute to the infiltration of CD4+ lymphocytes into synovial tissues. This mode of IL-16 induction represents a novel pathway leading to IL-16 production in RA-SF but not in OA-SF, and it operates independently of NFκB signaling.
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