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Urokinase [urokinase-type plasminogen activator (u-PA)] is potentially involved in the control of epithelial cell adhesion and repair processes. This study aimed to identify abnormalities in the responses in vitro of the u-PA system in colonic crypt cells in ulcerative colitis and Crohn's disease. Initial experiments demonstrated expression and transcription of receptors for u-PA (u-PAR) by colonic crypt cells. Differences across disease groups were found in results from cells isolated from noninflamed segments of colon. Supernatant and cell-associated u-PA activities in ulcerative colitis were significantly greater than normal, and supernatant u-PA activity was greater than in Crohn's disease. These differences were only partly explained by increased u-PA secretion compared with normal and lower plasminogen activator inhibitor-1 (PAI-1) secretion than in Crohn's disease. The effect of 20-h exposure to butyrate (1 mmol/ L) was similar across disease groups except for a failure to stimulate PAI-1 secretion in ulcerative colitis and Crohn's disease and to suppress u-PAR expression in Crohn's disease. In ulcerative colitis, colonic crypt cells from inflamed mucosa exhibited significantly lower cell-associated and supernatant u-PA activities and altered butyrate-mediated responses in cell-associated u-PA activity and u-PAR expression than cells from uninflamed mucosa. Perturbed colonic crypt cell responses of the u-PA system in vitro in ulcerative colitis suggest the presence of a primary diffuse abnormality in the colonic epithelium.