Goblet cell depletion occurs in various forms of
colitis, but its mechanism is unknown. We have investigated two linked hypotheses: (i) that bacterial
peptides, such as formyl-
methionyl-leucyl-phenylalanine (fMLP), interact with epithelial cells inducing the release of
chemokines, including
interleukin-8 (IL-8), which in turn leads to the recruitment of neutrophils which release
mucin secretagogues; (ii) that fMLP acts directly on epithelial cells to cause mucus secretion. Studies were performed to measure the effects of fMLP on the synthesis and secretion of
IL-8 and mucus by the goblet cell differentiated
colon cancer cell lines HT29-MTX (
methotrexate-conditioned HT29 colonic
adenocarcinoma cell line) and LS174T, and to assess the effects of neutrophil-derived
secretagogues on goblet cell secretion in these cell lines. fMLP (0.1 microM) increased the secretion of
IL-8 by 105% (P<0.0001) in HT29-MTX cells and by 401% (P<0.0001) in LS174T cells. fMLP also increased the synthesis and secretion of
mucins by these cell lines, with maximal effects of 65% above control values for synthesis (P<0.01) and 73% for secretion (P<0.01). A dose-related increase (up to 67%; P<0.01) in
mucin secretion was demonstrated in HT29-MTX cells in response to incubation with supernatant from activated neutrophils. This effect was largely (83%; P<0.02) inhibited by ICI 200,355, a specific inhibitor of
neutrophil elastase. In conclusion, the bacterial
peptide fMLP and
neutrophil elastase are both potent mucus
secretagogues for colon epithelial cells. fMLP also elicits release of the potent neutrophil
chemoattractant IL-8 from colon epithelial cells. These findings support the hypothesis that the mucosal
inflammation and mucus depletion seen in
ulcerative colitis could result from interaction between bacterial
peptides and the mucosa.