Cigarette Smoke Condensate Extracts Induce IL-1-Beta Production from Rheumatoid Arthritis Patient-Derived Synoviocytes, but Not Osteoarthritis Patient-Derived Synoviocytes, Through Aryl Hydrocarbon Receptor-Dependent NF-Kappa-B Activation and Novel NF-Kappa-B Sites

Cigarette smoking is a major established environmental risk factor for rheumatoid arthritis (RA), and synoviocyte-derived proinflammatory cytokines are implicated in the pathogenesis of RA. We have reported that aryl hydrocarbon or cigarette smoke condensate (CSC) is able to upregulate the production of proinflammatory cytokines from an RA patient-derived synovial fibroblast cell line MH7A. In this study, we compared the effect of CSC on induction of interleukin-1 beta (IL-1 beta) from RA or osteoarthritis (OA) patient-derived synovial fibroblasts, and studied the mechanism of the effect of CSC. CSC induced IL-1 beta mRNA from RA patient-derived synoviocytes and MH7A, but not from OA patient-derived synoviocytes. CSC induced the mRNA and both precursor and mature forms of IL-1 beta, and caspase-1 activity in MH7A. The mechanism of CSC-induced IL-1 beta mRNA expression was investigated in MH7A. Reporter gene analyses and promoter pull-down assay indicated that 3 novel NF-kappa B sites at -3771 to -3762 bp, -3105 to -3096 bp, and -2787 to -2778 bp in the promoter region of the IL-1 beta gene, especially the far distal NF-kappa B site and NF-kappa B activation, are critical for the gene activation by CSC. CSC-induced NF-kappa B activation, IL-1 beta promoter activity, IL-1 beta mRNA upregulation, and CYP1A1 mRNA induction were all inhibited by an aryl hydrocarbon receptor (AhR) antagonist alpha-naphthoflavone. These results indicate that CSC induced IL-1 beta production from RA patient-derived synoviocytes, but not OA patient-derived synoviocytes, through AhR-dependent NF-kappa B activation and novel NF-kappa B sites.