Activated endothelial cells elicit paracrine induction of epithelial chloride secretion. 6-Keto-PGF1alpha is an epithelial secretagogue.
Endothelial cells play a central role in the coordination of the inflammatory response. In mucosal tissue, such as the lung and intestine, endothelia are anatomically positioned in close proximity to epithelia, providing the potential for cell-cell crosstalk. Thus, in this study endothelial-epithelial biochemical crosstalk pathways were studied using a human intestinal crypt cell line (T84) grown in noncontact coculture with human umbilical vein endothelia. Exposure of such cocultures to endothelial-specific agonists (LPS) resulted in activation of epithelial electrogenic Cl- secretion and vectorial fluid transport. Subsequent experiments revealed that in response to diverse stimuli (LPS, IL-1alpha, TNF-alpha, hypoxia), endothelia produce and secrete a small, stable epithelial secretagogue into conditioned media supernatants. Further experiments identified this secretagogue as 6-keto-PGF1alpha, a stable hydrolysis product of prostacyclin (PGI2). Results obtained with synthetic prostanoids indicated that 6-keto-PGF1alpha (EC50 = 80 nM) and PGI2 stable analogues (EC50 = 280 nM) activate the same basolaterally polarized, Ca2+-coupled epithelial receptor. In summary, these findings reveal a previously unappreciated 6-keto-PGF1alpha receptor on intestinal epithelia, the ligation of which results in activation of electrogenic Cl- secretion. In addition, these data reveal a novel action for the prostacyclin hydrolysis product 6-keto-PGF1alpha and provide a potential endothelial- epithelial crosstalk pathway in mucosal tissue.
Blume
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ED
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Brigham and Women's Hospital, and Department of Cardiology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Taylor
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CT
Lennon
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PF
Stahl
G L
GL
Colgan
S P
SP
D015121:6-Ketoprostaglandin F1 alpha / Q000031:analogs & derivatives / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D016764:Cell Polarity; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism*; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D051546:Cyclooxygenase 2; D004730:Endothelium, Vascular / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology*; D011464:Epoprostenol / Q000031:analogs & derivatives; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins; D019899:Paracrine Communication; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002712:Chlorides; D017077:Culture Media, Conditioned; D007375:Interleukin-1; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011453:Prostaglandins; D011982:Receptors, Prostaglandin; D014409:Tumor Necrosis Factor-alpha; C034671:prostaglandin F2alpha receptor; D015121:6-Ketoprostaglandin F1 alpha; D002217:Carbachol; D011464:Epoprostenol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases