The expression of HLA-DR antigens on the surface of immune cells is crucial for appropriate antigen presentation and a normal immune response. In the intestinal mucosa involved by Crohn's disease and ulcerative colitis the expression of HLA-DR antigens is increased in both immune and nonimmune cells, a phenomenon probably mediated by soluble factors, such as interferon gamma, produced by locally activated mononuclear cells. This study investigated the production of interferon gamma by inflammatory bowel disease and control intestinal lamina propria mononuclear cells, and the ability of this endogenously produced lymphokine to induce expression of HLA-DR antigens on the monocytic cell lines U937 and ML3. After in vitro stimulation with interleukin 2 or phytohemagglutinin, but not spontaneously, lamina propria mononuclear cells produced variable amounts of interferon gamma, and their culture supernatants could induce de novo expression of HLA-DR antigens on the monocytic indicator cells. When the mononuclear cells were derived from inflammatory bowel disease mucosa, both the amount of interferon gamma present in the supernatants and the number of HLA-DR-positive cells induced by these supernatants were decreased as compared to controls. These results suggest that, in inflammatory bowel disease, interferon gamma may not be the only mediator of HLA-DR induction in the gut and that other soluble factors or agents, alone or interacting with interferon gamma, may also be responsible for this event, resulting in the enhanced HLA-DR antigen expression observed in the inflamed intestinal mucosa.