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Inhibitors of tumor necrosis factor α (TNFα) have demonstrated significant efficacy in chronic inflammatory diseases, including Crohn's disease (CD). To further elucidate the mechanisms of action of these agents, we compared the anti-TNFα agents certolizumab pegol, infliximab, adalimumab, and etanercept in several in vitro systems.The ability of each anti-TNFα agent to neutralize soluble and membrane-bound TNFα; mediate cytotoxicity, affect apoptosis of activated human peripheral blood lymphocytes and monocytes; induce degranulation of human peripheral blood granulocytes, and modulate lipopolysaccharide (LPS)-induced interleukin (IL)-1β production by human monocytes was measured in vitro.All 4 agents neutralized soluble TNFα and bound to and neutralized membrane TNFα. Infliximab and adalimumab were comparable in their ability to mediate complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity, and to increase the proportion of cells undergoing apoptosis and the level of granulocyte degranulation. Etanercept generally mediated these effects to a lesser degree, while certolizumab pegol gave similar results to the control reagents. LPS-induced IL-1β production was inhibited by certolizumab pegol, infliximab, and adalimumab, but only partially inhibited by etanercept.In contrast to the other anti-TNFα agents tested, certolizumab pegol did not mediate increased levels of apoptosis in any of the in vitro assays used, suggesting that these mechanisms are not essential for the efficacy of anti-TNFα agents in CD. As certolizumab pegol, infliximab, and adalimumab, but not etanercept, almost completely inhibited LPS-induced IL-1β release from monocytes, inhibition of cytokine production may be important for efficacy of anti-TNFα agents in CD.