Amphiregulin promotes intestinal epithelial regeneration: roles of intestinal subepithelial myofibroblasts.
Epidermal growth factor family plays critical roles in intestinal epithelial proliferation and differentiation. The precise function of amphiregulin (AREG), a member of the epidermal growth factor family, in intestinal biology is largely unknown. The present study attempted to address the functional roles of AREG in intestinal epithelial regeneration. Total body irradiation was performed, and intestinal regeneration was assessed in AREG knockout mice. Genetically disruption of AREG significantly impaired intestinal regeneration after radiation injury. It is known that prostaglandin E(2) (PGE(2)) exerts radio-protective and growth-stimulatory effects on intestinal epithelium. We found that PGE(2) radio-protective action did not involve AREG. However, PGE(2) growth-stimulatory effects required functional AREG. Localization of AREG expression was determined by immunohistochemistry in regenerative intestine. The immunoreactivity of AREG was predominantly localized in intestinal subepithelial myofibroblasts (ISEMF). Primary ISEMF cultures were established, and growth-stimulatory actions of ISEMF-generated AREG were demonstrated in cell coculture system. In addition, we found that the cAMP/protein kinase A pathway robustly induced AREG in cultured ISEMF. These studies suggest that AREG plays critical roles in intestinal epithelial growth. Modulation of levels of AREG by targeting ISEMF represents a novel strategy for treatment of certain intestinal disorders.
Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Jinyi
J
Shao
Hongmiao
H
Sheng
D066258:Amphiregulin; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D015232:Dinoprostone / Q000494:pharmacology; D066255:EGF Family of Proteins; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007410:Intestinal Diseases / Q000209:etiology / Q000235:genetics / Q000534:rehabilitation / Q000628:therapy; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000502:physiology* / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011833:Radiation Injuries, Experimental / Q000150:complications / Q000534:rehabilitation; D011837:Radiation-Protective Agents / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects
D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D011837:Radiation-Protective Agents; D015232:Dinoprostone