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1 have distinct effects on phenotype and
proliferation of intestinal fibroblasts
1 Department of Cell and Molecular Physiology and 2 Center for Gastrointestinal Biology and Disease, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7545
Insulin-like growth factor I (IGF-I)
and transforming growth factor-
1 (TGF-
1) are upregulated in
myofibroblasts at sites of fibrosis in experimental enterocolitis and
in Crohn's disease (CD). We compared the sites of expression of IGF-I
and TGF-
1 in a rat peptidoglycan-polysaccharide (PG-PS) model of
chronic granulomatous enterocolitis and fibrosis. We used the human
colonic CCD-18Co fibroblast/myofibroblast cell line to test the
hypothesis that TGF-
1 and IGF-I interact to regulate proliferation,
collagen synthesis, and activated phenotype typified by expression of
-smooth muscle actin and organization into stress fibers.
IGF-I potently stimulated while TGF-
1 inhibited basal DNA synthesis.
TGF-
1 and IGF-I each had similar but not additive effects to induce type I collagen. TGF-
1 but not IGF-I potently stimulated expression of
-smooth muscle actin and stress fiber formation. IGF-I in combination with TGF-
1 attenuated stress fiber formation without reducing
-smooth muscle actin expression. Stress fibers were not a
prerequisite for increased collagen synthesis. TGF-
1 upregulated IGF-I mRNA, which led us to examine the effects of IGF-I in cells previously activated by TGF-
1 pretreatment. IGF-I potently
stimulated proliferation of TGF-
1-activated myofibroblasts without
reversing activated fibrogenic phenotype. We conclude that TGF-
1 and
IGF-I both stimulate type I collagen synthesis but have differential effects on activated phenotype and proliferation. We propose that during intestinal inflammation, regulation of activated phenotype and
proliferation may require sequential actions of TGF-
1 and IGF-I, but
they may act in concert to increase collagen deposition.
Crohn's disease;
-smooth muscle actin; fibrosis
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