Differential autocrine regulation of intestine epithelial cell proliferation and differentiation by insulin-like...

The mechanisms which regulate cell turnover in the intestinal epithelium are incompletely understood. The present study was performed to characterize the role of autocrine IGF system components in intestine epithelial cell proliferation and differentiation comparing rapidly growing crypt cells (IEC-6) with differentiating enterocytes (CaCo-2). The autocrine release of IGF-I, IGF-II and IGFBP-1 through -3 was determined by specific RIAs and western ligand blotting. In addition, binding and growth-promoting activity of insulin, IGF-I and IGF-II was investigated. Enterocytic differentiation was assessed by measuring the brush-border enzymes alkaline phosphatase and sucrase. During IEC-6 growth, the autocrine release of IGF-I and -II increased, whereas IGFBP-2 levels decreased. Specific receptors for IGF-I and IGF-II but not insulin could be detected. IGF-I was 100-fold more potent than insulin to stimulate IEC-6 cell proliferation. In contrast, CaCo-2 cells revealed higher binding of insulin than IGF-I/-II and no release of IGF-I. At switch from CaCo-2 cell proliferation to differentiation a marked increase in the secretion of IGF-II (10-fold), IGFBP-1 (2.5-fold), IGFBP-2 (3-fold), and IGFBP-3 (6-fold) was measured. Our data indicate that IGF system components differentially modulate enterocytic cell proliferation and differentiation.