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IGF-I increases IGFBP-5 and collagen ₁(I) mRNAs by the MAPK pathway in rat intestinal smooth muscle cells

Departments of ¹Internal Medicine, ⁴Neurology, ³Obstetrics and Gynecology, and ⁵Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan 48109; and ²Shanghai Institute of Materia Medica, Shanghai, China 201203

Submitted 11 July 2003 ; accepted in final form 18 December 2003

IGF-I is a potent fibrogenic growth factor that stimulates proliferation of intestinal smooth muscle cells and increases synthesis of collagen and IGF-I-binding proteins by the cells. These processes contribute to intestinal fibrosis that develops in patients with Crohn's disease and in Lewis-strain rats with experimental Crohn's disease. The aim of this study was to determine which early docking proteins are associated with IGF-I receptor signal transduction and which transduction pathway is involved in IGF-I-mediated gene regulation in intestinal smooth muscle cells. Primary cultures of smooth muscle cells isolated from the muscularis externa of the distal colon of Lewis rats were treated with IGF-I (100 ng/ml). Immunoprecipitation studies demonstrated that IGF-I stimulation resulted in tyrosine phosphorylation of IRS-1, IRS-2, and Shc. Coimmunoprecipitation demonstrated a close association between the IGF-I receptor and these three early docking proteins. Concurrent treatment with the MAPK inhibitor PD98059 (10 µM) resulted in an inhibition of the IGF-I-mediated increase in IGFBP-5 and collagen ₁(I) mRNAs, while concurrent treatment with the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin (100 nM) had no effect. In additional experiments, cells were transiently transfected with adenoviral vectors dominantly expressing inactive mutant Akt or constitutively expressing wild-type Akt. In both cases, the IGF-I-mediated increase in collagen I protein did not differ from that observed in control cultures that had been transfected with an adenoviral vector carrying the LacZ reporter gene. These results suggest that the MAPK pathway is key to IGF-I-mediated gene regulation in intestinal smooth muscle cells, whereas data do not suggest a role for the Akt-dependent pathway in our system.

insulin-like growth factor I; signal transduction; Crohn's disease; inflammatory bowel disease

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