Autocrine and paracrine actions of intestinal fibroblast-derived insulin-like growth factors

Paracrine and autocrine actions of the insulin-like growth factors (IGFs) a re inferred by local expression within the bowel. CCD-18Co cells, IEC-6 cel ls, and immunoneutralization were used to analyze whether IGFs have direct autocrine or paracrine effects on proliferation of cultured intestinal fibr oblasts and epithelial cells. Growth factor expression was analyzed by ribo nuclease protection assay and RT-PCR. Extracellular matrix (ECM) was analyz ed for effects on cell proliferation. CCD-18Co cells express IGF-II mRNAs a nd low levels of IGF-I mRNA. Conditioned medium from CCD-18Co cells (CCD-CM ) stimulated proliferation of IEC-B and CCD-18Co cells. Neutralization of I GF immunoreactivity in CCD-CM reduced but did not abolish this effect. RT-P CR and immunoneutralization demonstrated that other growth factors contribu te to mitogenic activity of CCD-CM. Preincubation of CCD-CM with ECM prepar ed from IEC-6 or CCD-18Co cells reduced its mitogenic activity. ECM from CC D-18Co cells enhanced growth factor-dependent proliferation of IEC-6 cells. IEC-B cell ECM inhibited IGF-I;action on CCD-18Co cells. We conclude that IGF-II is a potent autocrine mitogen for intestinal fibroblasts. IGF-II int eracts with other fibroblast-derived growth factors and ECM to stimulate pr oliferation of intestinal epithelial cells in a paracrine manner.