Coordinated control of fetal gastric epithelial functions by insulin-like growth factors and their binding proteins

The influence of insulin-like growth factors (IGFs) and their binding prote ins (IGFBPs) on human gastric functions are unknown. This study was underta ken to evaluate the ability of fetal gastric mucosa to produce IGFBPs and t o test the effects of IGF-I, IGF-II, and synthetic truncated IGFs that do n ot interact with IGFBPs on epithelial cell proliferation and glandular zymo genic function. Western blots, Far Western blots, and immunohistochemistry were performed to characterize the expression of IGFBP-1 to -6 and IGF-I re ceptor. The effects of growth factors on DNA synthesis and lipase and pepsi n activities were determined in gastric explants maintained in serum-free o rgan culture. All gastric epithelial cells expressed the IGF-I receptor. IG FBP-2 to -6 were produced endogenously, and they were differentially locali zed along the foveolus-gland axis and modulated in culture. Exogenous IGF-I and IGF-II were able to reduce lipase activity without affecting pepsin, w hereas they exerted different effects on cellular proliferation: IGF-I was stimulatory and IGF-II had no influence, Illustrating the complex regulator y effect that IGFBPs exert on IGF bioactivity, both truncated IGF-I and IGF -II stimulated DNA synthesis more than IGF-I. Moreover, the striking differ ence in mitogenic activity between truncated and native forms of IGF-II pro bably reflects the abundance of IGFBP-2 and IGFBP-6, two IGF-II carriers, i n the foveolus/neck region, including the proliferative compartment. This s tudy provides new evidence for the involvement of an intragastric IGF/IGFBP system in the fine regulation of epithelial cell division and also in the control of zymogen synthesis. Moreover, the specific influence of IGF-II as a mitogen appears to be tightly regulated by IGFBP isoforms preferentially associated with this growth factor and proliferative cells.