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MUCOSAL BIOLOGY

Heregulin- and heregulin- expression is linked to a COX-2-PGE₂ pathway in human gastric fibroblasts

Third Department of Internal Medicine, Nippon Medical School, Bunkyo-ku, Tokyo, Japan

Submitted 1 June 2005 ; accepted in final form 8 December 2005

We have previously shown heregulin (HRG)- expression in human gastric fibroblasts and its stimulation of gastric epithelial cell growth. Although cyclooxygenase (COX)-2 has also been shown to stimulate growth factor production in these cells, the interaction between COX-2 and HRG remains unknown. Conditioned media (CM) from gastric fibroblasts incubated with PGE₂ or interleukin (IL)-1, a well known COX-2 inducer, were analyzed for their effect on erbB3 tyrosine phosphorylation in MKN28 gastric epithelial cells. HRG protein expression in fibroblast lysates and CM was also examined by western blot. HRG- and HRG- mRNA expression in gastric fibroblasts and human gastric tissue was examined by real-time quantitative PCR. HRG and COX-2 expressions in surgical resections of human gastric ulcer tissue were examined immunohistochemically. CM from fibroblasts incubated with PGE₂, or IL-1, stimulated erbB3 phosphorylation in MKN28 cells. Preincubation of the fibroblasts with celecoxib, a selective COX-2 inhibitor, suppressed CM-induced erbB3 phosphorylation. This inhibition was reversed by exogenous PGE₂. As with erbB3 phophorylation, IL-1 stimulated both HRG- and HRG- mRNA expression, as well as HRG release into gastric fibroblast CM. IL-1-stimulated HRG expression and release were also inhibited by celecoxib, and exogenous PGE₂ restored this inhibitory effect, suggesting the activation of an IL-1-COX-2-PGE₂ pathway that culminates in the release of HRG from fibroblasts. HRG- and HRG- mRNA levels were significantly higher in gastric ulcer tissue than in normal gastric mucosa. HRG immunoreactivity was found in interstitial cells of the gastric ulcer bed and coexpressed with COX-2. These results suggest that HRG might be a new member of the growth factor family involved in the COX-2-dependent ulcer repair process.

cyclooxygenase-2