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Am J Physiol Gastrointest Liver Physiol (December 18, 2003). doi:10.1152/ajpgi.00112.2003
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Submitted on March 11, 2003
Accepted on December 11, 2003

Stromal cell-derived factor-1/CXCL12 regulates cyclic AMP production and ion transport in intestinal epithelial cells via CXCR4

Michael B. Dwinell1*, Hiroyuki Ogawa1, Kim E. Barrett1, and Martin F. Kagnoff1

1 Department of Medicine, University of California, San Diego, La Jolla, CA, USA

* To whom correspondence should be addressed. E-mail: mdwinell{at}mcw.edu.

Human colonic epithelial cells express CXCR4, the sole cognate receptor for the chemokine stromal cell-derived factor (SDF)-1/CXCL12. The aim of this study was to define the mechanism and functional consequences of signaling intestinal epithelial cells through the CXCR4 chemokine receptor. CXCR4, but not SDF-1/CXCL12, was constitutively expressed by T84, HT-29, HT-29/18C1, and Caco-2 human colon epithelial cell lines. Studies using T84 cells showed that CXCR4 was G-protein coupled in intestinal epithelial cells. Moreover, stimulation of T84 cells with SDF-1/CXCL12 inhibited cAMP production in response to the adenylyl cyclase activator forskolin, and this inhibition was abrogated by either anti-CXCR4 antibody or receptor desensitization. Studies with pertussis toxin suggested SDF-1/CXCL12 activated negative regulation of cAMP production through G{alpha}i-subunits coupled to CXCR4. Consistent with the inhibition of forskolin-stimulated cAMP production, SDF-1/CXCL12 also inhibited forskolin-induced ion transport in voltage clamped polarized T84 cells. Taken together, these data indicate that epithelial CXCR4 can transduce functional signals in human intestinal epithelial cells that modulate important cAMP mediated cellular functions.




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