leukotriene-c4 and Crohn-Disease

We have described a novel macrophage-derived mucin secretagogue (MMS-68) that mediates mucin secretion in colon cancer cell lines and explants of normal and inflammatory bowel disease (IBD) mucosa. We compared MMS-68 induced mucin release with other known intestinal mucin secretagogues in normal colon explants and in the HT-29 colon cancer cell line, and to study the effects of MMS-68 on mucin release from inflamed and uninflamed ulcerative colitis (UC) and Crohn's disease (CD) mucosa. In normal colonic explants and HT-29 cells, each of the secretagogues including, MMS-68-induced mucin release two- to fivefold more than culture medium alone. In HT-29 cells, MMS-68 plus leukotriene C4 (LTC4) induced a 50% increase in mucin release over either secretagogue alone, and MMS-68 plus platelet-activating factor (PAF) markedly enhanced mucin release by eightfold over either secretagogue. In colonic explants from patients with UC and CD, the mucin release in response to MMS-68 was similar to that of normal colonic explants. Likewise, in isolated epithelial cells from CD and UC (whether involved or uninvolved), MMS-68-induced release was similar to that of epithelial cells isolated from normal colonic mucosa. The number of MMS-68-producing macrophages was lower in uninflamed UC mucosa compared with inflamed UC mucosa and CD mucosa. The mucin secretagogue activity of MMS-68 is comparable to that of other known secretagogues, and PAF can have a synergistic effect on this activity. Whole tissue explants and isolated colonic epithelial cells from patients with IBD respond at least as well as their normal counterparts to MMS-68. MMS-68 may play a role in mucin secretion in normal and inflamed colonic tissue.

Topics: Carbachol; Colitis, Ulcerative; Colorectal Neoplasms; Crohn Disease; Epithelial Cells; Glycoproteins; Humans; In Vitro Techniques; Intestinal Secretions; Leukotriene C4; Macrophages; Mucins; Platelet Activating Factor; Tumor Cells, Cultured

The mucosal release of inflammatory mediators is enhanced in active inflammatory bowel disease. This study examines whether leukotriene C4 production occurs in apparently unaffected segments of the gut. The intraluminal release of leukotriene C4 was determined by jejunal perfusion in seven healthy controls, in nine patients with chronic ulcerative colitis, and in 13 patients with Crohn's disease (six with ileal disease, and seven with only colonic). All patients were in clinical remission and none of them had evidence of jejunal involvement. Mild intraluminal irritation with a 2.5 mmol/l deoxycholic acid solution was induced to stimulate local inflammatory mechanisms. The release of DNA (a marker of mucosal desquamation) and prostaglandin E2 (PGE2) was simultaneously measured. Jejunal release of DNA was higher in Crohn's disease patients than in ulcerative colitis or healthy controls. Basal release of PGE2 was similar in the three groups of patients. Basal release of leukotriene C4 was considerably enhanced, however, in Crohn's disease patients compared with healthy controls. In ulcerative colitis patients, basal leukotriene C4 release was non-significantly different from controls. Bile acid perfusion stimulated PGE2, leukotriene C4, and DNA release in all groups studied, but leukotriene C4 release was significantly higher in Crohn's disease patients. It is concluded that in inactive Crohn's disease there is an enhanced intraluminal release of leukotriene C4 in apparently unaffected segments of proximal small bowel, which may reflect fundamental changes in the function of the gut mucosal barrier.

Topics: Adult; Aged; Body Water; Colitis, Ulcerative; Crohn Disease; Dinoprostone; Female; Humans; Intestinal Mucosa; Jejunum; Leukotriene C4; Male; Middle Aged