Mechanism of Action of Glucagon-Like Peptide-2 to Increase IGF-I mRNA in Intestinal Subepithelial Fibroblasts

  • Jason L. S. Leen
    Departments of Physiology (J.L.S.L., A.I., C.U., K.J.R., P.E.D., S.G., S.P.H., P.L.B.), University of Toronto, Toronto, Ontario, Canada M5S 1A8
  • Angelo Izzo
    Departments of Physiology (J.L.S.L., A.I., C.U., K.J.R., P.E.D., S.G., S.P.H., P.L.B.), University of Toronto, Toronto, Ontario, Canada M5S 1A8
  • Chandani Upadhyay
    Departments of Physiology (J.L.S.L., A.I., C.U., K.J.R., P.E.D., S.G., S.P.H., P.L.B.), University of Toronto, Toronto, Ontario, Canada M5S 1A8
  • Katherine J. Rowland
    Departments of Physiology (J.L.S.L., A.I., C.U., K.J.R., P.E.D., S.G., S.P.H., P.L.B.), University of Toronto, Toronto, Ontario, Canada M5S 1A8
  • Philip E. Dubé
    Departments of Physiology (J.L.S.L., A.I., C.U., K.J.R., P.E.D., S.G., S.P.H., P.L.B.), University of Toronto, Toronto, Ontario, Canada M5S 1A8
  • Steven Gu
    Departments of Physiology (J.L.S.L., A.I., C.U., K.J.R., P.E.D., S.G., S.P.H., P.L.B.), University of Toronto, Toronto, Ontario, Canada M5S 1A8
  • Scott P. Heximer
    Departments of Physiology (J.L.S.L., A.I., C.U., K.J.R., P.E.D., S.G., S.P.H., P.L.B.), University of Toronto, Toronto, Ontario, Canada M5S 1A8
  • Christopher J. Rhodes
    Kovler Diabetes Center (C.J.R.), University of Chicago, Chicago, Illinois 60637
  • Daniel R. Storm
    Department of Pharmacology (D.R.S.), University of Washington, Seattle, Washington 98195
  • P. Kay Lund
    Department of Cell and Molecular Physiology (P.K.L.), University of North Carolina, Chapel Hill, North Carolina 27510
  • Patricia L. Brubaker
    Departments of Physiology (J.L.S.L., A.I., C.U., K.J.R., P.E.D., S.G., S.P.H., P.L.B.), University of Toronto, Toronto, Ontario, Canada M5S 1A8

抄録

<jats:title>Abstract</jats:title><jats:p>IGF-I, a known secretory product of intestinal subepithelial myofibroblasts (ISEMFs), is essential for the intestinotropic effects of glucagon-like peptide-2 (GLP-2). Furthermore, GLP-2 increases IGF-I mRNA transcript levels in vitro in heterogeneous fetal rat intestinal cultures, as well as in vivo in the rodent small intestine. To determine the mechanism underlying the stimulatory effect of GLP-2 on intestinal IGF-I mRNA, murine ISEMF cells were placed into primary culture. Immunocytochemistry showed that the ISEMF cells appropriately expressed α-smooth muscle actin and vimentin but not desmin. The cells also expressed GLP-2 receptor and IGF-I mRNA transcripts. Treatment of ISEMF cells with (Gly2)GLP-2 induced IGF-I mRNA transcripts by up to 5-fold of basal levels after treatment with 10−8m GLP-2 for 2 h (P &lt; 0.05) but did not increase transcript levels for other intestinal growth factors, such as ErbB family members. Immunoblot revealed a 1.6-fold increase in phospho (p)-Akt/total-(t)Akt with 10−8m GLP-2 treatment (P &lt; 0.05) but no changes in cAMP, cAMP-dependent β-galactosidase expression, pcAMP response element-binding protein/tcAMP response element-binding protein, pErk1/2/tErk1/2, or intracellular calcium. Furthermore, pretreatment of ISEMF cells with the phosphatidylinositol 3 kinase (PI3K) inhibitors, LY294002 and wortmannin, abrogated the IGF-I mRNA response to GLP-2, as did overexpression of kinase-dead Akt. The role of PI3K/Akt in GLP-2-induced IGF-I mRNA levels in the murine jejunum was also confirmed in vivo. These findings implicate the PI3K/Akt pathway in the stimulatory effects of GLP-2 to enhance intestinal IGF-I mRNA transcript levels and provide further evidence in support of a role for IGF-I produced by the ISEMF cells in the intestinotropic effects of GLP-2.</jats:p>

収録刊行物

  • Endocrinology

    Endocrinology 152 (2), 436-446, 2010-12-15

    The Endocrine Society

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