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.