Selective resistance of mucosal T-cell activation to immunosuppression in Crohn's disease.
OBJECTIVE
The inappropriately high state of T-cell activation found in Crohn's disease could be due to failure to respond to inhibitory signals. We tested the hypothesis that Crohn's disease mucosal T-cells are resistant to the immunosuppressive action of interleukin4.


METHODS
Patients with Crohn's disease, ulcerative colitis, and other malignant and non-malignant conditions undergoing bowel resection.


METHODS
The effect of interleukin-4 on lamina propria mononuclear cells from Crohn's disease, ulcerative colitis and control mucosa was assessed on various T-cell functions: interleukin-2-induced cytotoxicity, soluble interleukin-2 receptor and interleukin-2 production, and expression of mRNA for interleukin-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 inhibited. Addition of interleukin-4 to interleukin-2-stimulated cultures decreased soluble interleukin-2R production significantly less in Crohn's disease and ulcerative colitis than control cells. In the same cultures, residual levels of interleukin-2 were significantly increased in control and ulcerative colitis, but not Crohn's disease cultures. Finally, Crohn's disease cells were significantly more resistant to interleukin-4-mediated inhibition of spontaneous and interleukin-2-induced expression of interleukin-2Ralpha and interferon-gamma mRNA compared to control cells.


CONCLUSIONS
The effector function, receptor expression and cytokine production of Crohn's disease mucosal T-cells are resistant to interleukin4-mediated inhibition. Failure to respond to down-regulatory signals may contribute to persistent T-cell activation and chronicity of inflammation in Crohn's disease.
Matsuura
T
T
Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University, School of Medicine, OH 44106-4952, USA.
West
G A
GA
Levine
A D
AD
Fiocchi
C
C
D000293:Adolescent; D000328:Adult; D016923:Cell Death; D003424:Crohn Disease / Q000276:immunology*; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000276:immunology / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D015375:Receptors, Interleukin-2 / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*
D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D015847:Interleukin-4