Defective post-transcriptional processing of MUC2 mucin in ulcerative colitis and in Crohn's disease increases detectability of the MUC2 protein core

Ulcerative colitis (UC) and, to a lesser extent, Crohn's disease (CD) are a ssociated with a reduction of the protective mucus layer in the large intes tine; the role of this alteration in the pathogenesis of either disease is, however, not clear. To learn more about the molecular mechanism of the alt eration of the mucus layer, the expression of the main intestinal mucin, MU C2, was investigated in relation to inflammation and dysplasia. Formalin-fi xed, paraffin-embedded biopsies from 70 patients with UC and 16 patients wi th CD, and 13 biopsies from normal colonic mucosa, were used for detection of MUC2 mRNA by in situ hybridization with the SMUC41 probe, and MUC2 prote in by immunohistochemistry with the antibody CCP58. The steady-state concen tration of MUC2 mRNA was not affected by UC or CD. By contrast, the amount of the detectable MUC2 protein, assessed as the immunoreactive score (IRS), was significantly (p<0.0001) increased in UC (IRS=8.0 +/- 3.8) and CD (8.0 +/- 3.7), compared with the normal colonic mucosa (IRS=2.0 +/- 1.5). This alteration occurred in the inactive phase of inflammation and persisted in the active phase of the disease. It was also observed during bacterial or p rotozoal inflammation (n=7). The IRS values did not correlate with the grad e of inflammation or dysplasia. Simultaneous histochemistry with high iron diamine and immunohistochemistry indicated that the increase of detectable MUC2 is concomitant with low mucin sulphation in the same cells. These data indicate that the strong MUC2, protein staining in colonic mucosa of patie nts with UC or CD is due to a long-term alteration of the post-transcriptio nal modification of the MUC2 molecule, leading to its better detectability by the anti-MUC2 antibody CCP58. This alteration, induced by the inflammato ry process, may affect the gel thickness and may contribute to a protracted autoimmune response. (C) 1999 John Wiley & Sons, Ltd.