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OBJECTIVE: Rheumatoid arthritis (RA) is a disease characterized by prolonged production of tumor necrosis factor-alpha (TNF-alpha), which is regulated by the Rel/nuclear factor-kappaB (NF-kappaB) transcription factors. We assessed NF-kappaB activation in peripheral blood mononuclear cells (PBMC), peripheral blood lymphocytes (PBL), and monocytes from patients with RA, patients with ankylosing spondylitis (AS), and healthy subjects. METHODS: NF-kappaB activation was determined by electrophoretic mobility shift assays and by Western blotting in PBMC, monocytes, and PBL isolated from peripheral blood of patients with RA, patients with AS, and healthy subjects and determined after ex vivo pretreatment of PBMC, PBL, and monocytes of patients with RA and healthy subjects with infliximab and with etanercept. RESULTS: Enhanced NF-kappaB activation was observed in monocytes, PBL, and PBMC isolated from patients with RA, but not in PBMC, PBL, and monocytes of patients with AS and healthy subjects. The NF-kappaB complex was composed of p50 and p65 subunits and its activation required inhibitor of NF-kappaBalpha degradation. We observed a positive correlation between the NF-kappaB activation in monocytes, PBL, and PBMC, and TNF-alpha levels in peripheral blood of patients with RA. Ex vivo treatment with infliximab and etanercept decreased NF-kappaB activation in monocytes of patients with RA, but not in PBL and PBMC, and not in healthy subjects. CONCLUSION: Our results indicate a role for NF-kappaB activation and TNF-alpha in the activation of monocytes of patients with RA, and suggest an important role of circulating monocytes in RA pathogenesis.