OBJECTIVE In inflammatory bowel disease (IBD), peripheral monocytes and intestinal macrophages show an increased state of priming and activation. The aim of this study was to test the hypothesis that the response of IBD mononuclear phagocytes to the contrainflammatory cytokine interleukin (IL) 4 may be altered. METHODS The in vitro secretion of proinflammatory cytokines (IL-1 beta, tumor necrosis factor alpha [TNF-alpha], and IL-1-receptor antagonist [IL-1ra]) by peripheral monocytes and by intestinal lamina propria mononuclear cells (LPMNCs) was assessed by enzyme-linked immunosorbent assay. In parallel, superoxide anion release, macrophage mannose receptor, and IL-4 receptor expression were investigated. RESULTS IBD peripheral monocytes and intestinal LPMNCs in vitro secrete increased amounts of proinflammatory cytokines (IL-1 beta and TNF-alpha) with decreased IL-1ra/IL-1 beta ratios. IL-4 down-regulates proinflammatory cytokine (IL-1 beta and TNF-alpha) and superoxide anion secretion in a dose-dependent manner. In contrast to normal and disease-specific controls, IBD peripheral monocytes and IBD intestinal LPMNCs show a diminished responsiveness to the inhibitory effect of IL-4. The IL-1ra/IL-1 beta ratios in normal monocytes are increased by IL-4, whereas in IBD monocytes low IL-1ra/IL-1 beta ratios persist after IL-4 treatment. IL-4-induced expression of macrophage mannose receptor, which is a molecule pivotal to macrophage-mediated host defense, again appeared to be impaired in IBD monocytes. CONCLUSIONS IL-4-mediated regulation of mononuclear phagocyte effector functions is disturbed in IBD.