title: Macrophage-inflammatory protein-3alpha mediates epidermal growth factor receptor transactivation and ERK1/2 MAPK signaling in Caco-2 colonic epithelial cells via metalloproteinase-dependent release of amphiregulin.
abstract: Previously, we reported that normal colonocytes produce the memory CD4(+) T cell-directed chemokine MIP-3alpha, and that epithelial MIP-3alpha levels are elevated in inflammatory bowel disease. Interestingly, the unique receptor for MIP-3alpha, CCR6, is expressed by a variety of cell types including colonocytes, suggesting that MIP-3alpha may regulate additional biological activities in the intestine. The aim of this study was to determine whether MIP-3alpha can induce intestinal epithelial cell proliferation and to examine the signaling mechanisms that mediate this response. We show that nonstimulated Caco-2 and HT-29 colonic epithelial cells express CCR6, and that stimulation of Caco-2 cells by MIP-3alpha can dose dependently increase cell proliferation as well as activate the epidermal growth factor receptor (EGFR) and ERK1/2 MAPK. MIP-3alpha-mediated ERK1/2 activation in Caco-2 cells appeared to require metalloproteinase-dependent release of the endogenous EGFR ligand amphiregulin and transactivation of the EGFR. Moreover, blockade of amphiregulin bioactivity using a neutralizing polyclonal Ab significantly reduced MIP-3alpha-mediated, but not EGF-mediated Caco-2 cell proliferation. Taken together, our findings indicate that MIP-3alpha can regulate mitogenic signaling in colonic epithelial cells and thus may serve an important homeostatic function in the intestine by regulating tissue turnover and maintenance of the epithelium, in addition to its role in regulating leukocyte recruitment.
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Keates
authors.forename: Xinbing
authors.initials: X
authors.lastname: Han
authors.forename: Ciarán P
authors.initials: CP
authors.lastname: Kelly
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Keates
mesh_terms: D066258:Amphiregulin; D000911:Antibodies, Monoclonal; D018938:Caco-2 Cells; D049109:Cell Proliferation; D054418:Chemokine CCL20; D019742:Chemokines, CC / Q000378:metabolism* / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000276:immunology*; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000235:genetics*; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism* / Q000494:pharmacology; D045726:Metalloproteases / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D054399:Receptors, CCR6; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D000911:Antibodies, Monoclonal; C108355:CCL20 protein, human; C106311:CCR6 protein, human; D054418:Chemokine CCL20; D019742:Chemokines, CC; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D019402:Macrophage Inflammatory Proteins; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D045726:Metalloproteases