IGF-I and TGF-beta1 have distinct effects on phenotype and proliferation of intestinal fibroblasts.
Insulin-like growth factor I (IGF-I) and transforming growth factor-beta1 (TGF-beta1) 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-beta1 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-beta1 and IGF-I interact to regulate proliferation, collagen synthesis, and activated phenotype typified by expression of alpha-smooth muscle actin and organization into stress fibers. IGF-I potently stimulated while TGF-beta1 inhibited basal DNA synthesis. TGF-beta1 and IGF-I each had similar but not additive effects to induce type I collagen. TGF-beta1 but not IGF-I potently stimulated expression of alpha-smooth muscle actin and stress fiber formation. IGF-I in combination with TGF-beta1 attenuated stress fiber formation without reducing alpha-smooth muscle actin expression. Stress fibers were not a prerequisite for increased collagen synthesis. TGF-beta1 upregulated IGF-I mRNA, which led us to examine the effects of IGF-I in cells previously activated by TGF-beta1 pretreatment. IGF-I potently stimulated proliferation of TGF-beta1-activated myofibroblasts without reversing activated fibrogenic phenotype. We conclude that TGF-beta1 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-beta1 and IGF-I, but they may act in concert to increase collagen deposition.
Department of Cell and Molecular Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7545, USA. jgs@med.unc.edu
James G
JG
Simmons
Jolanta B
JB
Pucilowska
Temitope O
TO
Keku
P Kay
PK
Lund
D000199:Actins / Q000378:metabolism; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004760:Enterocolitis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D005347:Fibroblasts / Q000473:pathology* / Q000502:physiology*; D005355:Fibrosis; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000494:pharmacology; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D007422:Intestines / Q000473:pathology*; D009130:Muscle, Smooth / Q000378:metabolism; D010457:Peptidoglycan; D010641:Phenotype; D011134:Polysaccharides; D051381:Rats; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
D000199:Actins; D024042:Collagen Type I; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D010457:Peptidoglycan; D011134:Polysaccharides; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D007334:Insulin-Like Growth Factor I; D004247:DNA