KERATINOCYTE GROWTH-FACTOR INDUCES PROLIFERATION OF HEPATOCYTES AND EPITHELIAL-CELLS THROUGHOUT THE RAT GASTROINTESTINAL-TRACT

Keratinocyte growth factor (KGF), a member of the fibroblast growth fa ctor (FGF) family, was identified as a specific keratinocyte mitogen a fter isolation from a lung fibroblast line. Recently, recombinant (r)K GF was found to influence proliferation and differentiation patterns o f multiple epithelial cell lineages within skin, lung, and the reprodu ctive tract. In the present study, we designed experiments to identify additional target tissues, and focused on the rat gastrointestinal (G I) system, since a putative receptor, K-sam, was originally identified in a gastric carcinoma. Expression of KGF receptor and KGF mRNA was d etected within the entire GI tract, suggesting the gut both synthesize d and responded to KGF. Therefore, rKGF was administered to adult rats and was found to induce markedly increased proliferation of epithelia l cells from the foregut to the colon, and of hepatocytes, one day aft er systemic treatment. Daily treatment resulted in the marked selectiv e induction of mucin-producing cell lineages throughout the GI tract i n a dose-dependent fashion. Other cell lineages were either unaffected (e.g., Paneth cells), or relatively decreased (e.g., parietal cells, enterocytes) in rKGF-treated rats. The direct effect of rKGF was confi rmed by demonstrating markedly increased carcinoembryonic antigen prod uction in a human colon carcinoma cell line, LIM1899. Serum levels of albumin were specifically and significantly elevated after daily treat ment. These results demonstrate rKGF can induce epithelial cell activa tion throughout the GI tract and liver. Further, endogenous KGF may be a normal paracrine mediator of growth within the gut.