Induction of EGF-like Growth Factors and Epidermal Growth Factor Receptors by Interleukin-1β in Gastric Mucosa

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In this sturdy, we hypothesized IL-1β, proinflammatory cytokine, could exert some biological effects through expression of epidermal growth factor (EOF) family peptides in gastric mucosa. Therefore we examined the ability of IL-1β to induce EGF-like growth factors and EGF receptor (EGFR) in human gastric fibrodasts and 5 gastric cancer cell lines. Methods: Cultured cells were stimulated by IL-1β and the mRNA expression of transforming growth factor-α (TGF-α), heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin (AR) was examined by real-time PCR. TGF-α in the conditioned media (CM) obtained from culture cells was determined using a TGF-α ELISA kit. EGFR expression was examined by western blot analysis. Results: IL-1β increased mRNA levels of TGF-α, HB-EGF and AR in 4 gastric cancer cell lines. In contrast, a significant expression of TGF-α mRNA was not found in gastric fibroblasts. In the 4 gastric cancer cell lines, IL-1β stimulated TGF-α release into CM only in the presen … More ce of 12-myristate 13-acetate (PMA), which is known to induce a cleavaging enzyme of proTGF-α. Selective COX-2 inhibitors did not inhibit the TGF-α release by IL-1β, suggesting that this induction of TGF-α was not mediated by COX-2. Furthermore, IL-1β increased TGF-α expression more significantly in coculture of MKN28 cells and gastric fibroblasts than in separate cultivation, indicating there might be some epithelial-mesenchymal interaction in TGF-α induction by IL-1β. CM from gastric fibroblasts incubated with IL-1β stimulated TGF-α expression in MKN28 cells more significantly than control media, confirming our assumption. Contrary to TGF-α expression, IL-1β increased expression of EGFR in gastric fibroblasts, but not in MKN28 cells. Furthermore, IL-1β activated tyrosine phosphorylation of EGFR in coculture of MKN28 cells and gastric fibroblasts more markedly than in separate cultivation. Conclusion: IL-1β exerts its biological effects on the gastric mucosa through the induction of EGFR and EGF-like growth factors in epithelial-mesenchymal interaction. Less