Selective resistance of mucosal T-cell activation to immunosuppression in Crohn's disease

Background & Aims. The inappropriately high state of T-cell activation foun d in Crohn's disease could be due to failure to respond to inhibitory signa ls. We tested the hypothesis that Crohn's disease mucosal T-cells are resis tant to the immunosuppressive action of interleukin-4. Patients, Patients with Crohn's disease, ulcerative colitis, and other mali gnant and non-malignant conditions undergoing bowel resection. Methods, The effect of interleukin-4 on lamina propria mononuclear cells fr om Crohn's disease, ulcerative colitis and control mucosa was assessed on v arious T-cell functions: interleukin-2-induced cytotoxicity, soluble interl eukin-2 receptor and interleukin-2 production, and expression of mRNA for i nterleukin-2R and interferon-gamma. Results. Cytotoxicity of control and ulcerative colitis cells was markedly decreased by interleukin-4, whereas Crohn's disease cells failed to be inhi bited. Addition of interleukin-4 to interleukin-2-stimulated cultures decre ased soluble interleukin-2R production significantly less in Crohn's diseas e and ulcerative colitis than control cells. In the same cultures, residual levels of interleukin-2 were significantly increased in control and ulcera tive colitis, but not Crohn's disease cultures. Finally, Crohn's disease ce lls were significantly more resistant to interleukin-4-mediated inhibition of spontaneous and interleukin-2-induced expression of interleukin-2R alpha and interferon-gamma mRNA compared to control cells. Conclusions. The effector function, receptor expression and cytokine produc tion of Crohn's disease mucosal T-cells are resistant to interleukin-4-medi ated inhibition. Failure to respond to down-regulatory signals may contribu te to persistent T-cell activation and chronicity of inflammation in Crohn' s disease.