Endogenous IGF-I and alpha v beta3 integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis.
Endogenous insulin-like growth factor-I (IGF-I) regulates intestinal smooth muscle growth by concomitantly stimulating proliferation and inhibiting apoptosis. IGF-I-stimulated growth is augmented by the alpha(v)beta(3) integrin ligands vitronectin and fibronectin. IGF-I expression in smooth muscle is increased in both TNBS-induced colitis and Crohn's disease. We hypothesized that intestinal inflammation increased vitronectin and fibronectin expression by smooth muscle and, along with IGF-I upregulation, increased intestinal muscle growth. Intestinal smooth muscle cells were examined 7 days following the induction of TNBS-induced colitis. Although alpha(v)beta(3) integrin expression was not altered by TNBS-induced colitis, vitronectin and fibronectin levels were increased by 80 +/- 10% and 90 +/- 15%, above control levels, respectively. Basal IGF-I receptor phosphorylation in inflamed muscle from TNBS-treated rats was increased by 86 +/- 8% over vehicle-treated controls. Basal ERK1/2, p70S6 kinase, and GSK-3beta phosphorylation in muscle cells of TNBS-treated rats were also increased by 140-180%. TNBS treatment increased basal muscle cell proliferation by 130 +/- 15% and decreased apoptosis by 20 +/- 2% compared with that in vehicle-treated controls. The changes in proliferation and apoptosis were reversed by an IGF-I receptor tyrosine kinase inhibitor or an alpha(v)beta(3) integrin antagonist. The results suggest that smooth muscle hyperplasia in TNBS-induced colitis partly results from the upregulation of endogenous IGF-I and ligands of alpha(v)beta(3) integrin that mediate increased smooth muscle cell proliferation and decreased apoptosis. This paper has identified one mechanism regulating smooth muscle hyperplasia, a feature of stricture formation that occurs in the chronically inflamed intestine of TNBS-induced colitis and potentially Crohn's disease.
Department of Medicine, Medical College of Virginia Campus, Virginia Commonwealth Univ., PO Box 980711, Richmond, VA 23298-0711, USA.
Krystina B
KB
Hazelgrove
Robert S
RS
Flynn
Li-Ya
LY
Qiao
John R
JR
Grider
John F
JF
Kuemmerle
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced* / Q000150:complications / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006965:Hyperplasia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D009130:Muscle, Smooth / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology*; D019096:Vitronectin / Q000378:metabolism
D004791:Enzyme Inhibitors; D005353:Fibronectins; D039302:Integrin alphaVbeta3; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D010455:Peptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019096:Vitronectin; C057986:echistatin; D007334:Insulin-Like Growth Factor I; D014302:Trinitrobenzenesulfonic Acid; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3