Infliximab, a chimeric monoclonal antibody against TNF, is efficacious in Crohn's disease (CD) and rheumatoid arthritis (RA). Its main mechanism of action is thought to be the induction of apoptosis. The present study evaluates in detail the effects of infliximab on the TNF system using PB monocytes and T cells as well as lamina propria lymphocytes (LPLs) from normal individuals (NI) and patients with CD, ulcerative colitis (UC), and RA. Lymphocytes were studied in the resting state in the absence of strong stimuli that may obscure subtle findings. Infliximab did not change the numbers of viable cells. Rather, it caused monocytes to increase their release of soluble TNFR2 which serves to neutralize TNF, potentiating the action of infliximab. It reduced TNFR2 expression, thereby decreasing TNF responsiveness. These changes were due to up-regulated production of TNFR2 rather than increased shedding. Infliximab did not cause rebound production of TNF transcripts that would counteract its effects. It specifically enhanced production of IL-10 but not proinflammatory cytokines secreted by leukocytes, thereby promoting an anti-inflammatory microenvironment. In addition, infliximab caused a rise in c-Jun amino-terminal kinase (JNK) phosphorylation by monocytes. Thus, infliximab manipulates the TNF system to promote its anti-TNF effects.