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Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase activity and hence PG production. However, the ability of NSAIDs to ameliorate pain and tenderness does not prevent disease progression in rheumatoid arthritis, a disease whose pathogenesis is linked to the presence of proinflammatory cytokines, such as TNF-alpha. To understand this observation, we have examined the effect of NSAIDs on the production of clinically validated proinflammatory cytokines. We show that a variety of NSAIDs superinduce production of TNF from human peripheral blood monocytes and rheumatoid synovial membrane cultures. A randomized, double-blinded, crossover, placebo-controlled trial in healthy human volunteers also revealed that the NSAID drug celecoxib increased LPS-induced TNF production in whole blood. NSAID-mediated increases in TNF are reversed by either the addition of exogenous PGE(2) or by a PGE(2) EP2 receptor agonist, revealing that PGE(2) signaling via its EP2 receptor provides a valuable mechanism for controlling excess TNF production. Thus, by reducing the level of PGE(2), NSAIDs can increase TNF production and may exacerbate the proinflammatory environment both within the rheumatoid arthritis joint and the systemic environment.

Original publication




Journal article


J Immunol

Publication Date





3694 - 3701


Adult, Animals, Anti-Inflammatory Agents, Non-Steroidal, Antirheumatic Agents, Arthritis, Experimental, Arthritis, Rheumatoid, Celecoxib, Cells, Cultured, Cross-Over Studies, Cytokines, Double-Blind Method, Humans, Male, Mice, Mice, Inbred DBA, Middle Aged, Pyrazoles, Sulfonamides, Synovial Membrane, Tumor Necrosis Factor-alpha, Up-Regulation