Faculty Collaboration Database

CXCL12 activation of CXCR4 regulates mucosal host defense through stimulation of epithelial cell migration and promotion of intestinal barrier integrity. Am J Physiol Gastrointest Liver Physiol 2005 Feb;288(2):G316-26

Date

09/11/2004

Pubmed ID

15358596

DOI

10.1152/ajpgi.00208.2004

Scopus ID

2-s2.0-12344262717 (requires institutional sign-in at Scopus site)   86 Citations

Abstract

Intestinal epithelial cell migration plays a key role in gastrointestinal mucosal barrier formation, enterocyte development, differentiation, turnover, wound healing, and adenocarcinoma metastasis. Chemokines, through engagement of their corresponding receptors, are potent mediators of directed cell migration and are critical in the establishment and regulation of innate and adaptive immune responses. The aim of this study was to define the role for the chemokine CXCL12 and its sole cognate receptor CXCR4 in regulating intestinal epithelial cell migration and to determine its impact on barrier integrity. CXCL12 stimulated the dose-dependent chemotactic migration of human T84 colonic epithelial cells. Epithelial cell migration was inhibited by CXCR4 neutralizing antibody, pertussis toxin, LY-294002, and PD-98059, thereby implicating Galpha(i), phosphatidylinositol 3-kinase (PI3-kinase), and the ERK1/2 MAP kinase pathways in CXCR4-specific signaling. CXCL12 was also shown to increase barrier integrity, as defined by transepithelial resistance and paracellular flux across differentiating T84 monolayers. To determine whether CXCL12 regulated epithelial restitution, we used the normal nontransformed intestinal epithelial cell-6 (IEC-6) wound healing model. By using RT-PCR, immunoblot analysis, and immunofluorescence microscopy, we first showed expression of both CXCR4 and its ligand by IEC-6 cells. We then demonstrated that CXCL12 activated comparable signaling mechanisms to stimulate epithelial migration in the absence of proliferation in wounded IEC-6 monolayers. Taken together, these data indicate that CXCL12 signaling via CXCR4 directs intestinal epithelial cell migration, barrier maturation, and restitution, consistent with an important mechanistic role for these molecules in mucosal barrier integrity and innate host defense.

Author List

Smith JM, Johanesen PA, Wendt MK, Binion DG, Dwinell MB

Author

Michael B. Dwinell PhD Center Director, Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cell Line
Cell Line, Tumor
Cell Proliferation
Chemokine CXCL12
Chemokines, CXC
Chemotaxis
Extracellular Signal-Regulated MAP Kinases
Gene Expression
Humans
Immunity, Mucosal
Intestinal Mucosa
Phosphatidylinositol 3-Kinases
Rats
Receptors, CXCR4
Receptors, Chemokine
Signal Transduction
Wound Healing