Regulation of endothelin synthesis in hepatic endothelial cells.
Endothelin (ET) stimulates vasoconstriction and glucose production and mediator synthesis in the liver. Only hepatic endothelial cells express ET-1 mRNA, and during endotoxemia in the intact rat, a ninefold increase in hepatic ET-1 mRNA occurs within 3 h of lipopolysaccharide (LPS) infusion [A. T. Eakes, K. M. Howard, J. E.Miller, and M. S. Olson. Am. J. Physiol. 272 (Gastrointest. Liver Physiol. 35): G605-G611, 1997]. The present study defines the mechanism by which hepatic ET production is enhanced during endotoxin exposure. Culture media conditioned by exposure to endotoxin-treated Kupffer cells stimulated a twofold increase in immunoreactive ET-1 (irET-1) secretion by liver endothelial cells. Transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha), LPS, and platelet-activating factor (PAF) were tested for their ability to stimulate cultured liver endothelial cells to secrete irET-1. Although TNF-alpha, LPS, and PAF had no significant effect on ET-1 synthesis, TGF-beta increased ET-1 mRNA expression and irET-1 secretion. In coculture experiments, treating Kupffer cells with endotoxin caused a doubling of the ET-1 mRNA level in the liver endothelial cells.This increase in ET-1 mRNA was attenuated by a TGF-beta-neutralizing antibody. Hence, a paracrine signaling mechanism operates between Kupffer cells that release TGF-beta on endotoxin challenge and hepatic endothelial cells in which TGF-beta stimulates ET-1 mRNA expression and ET-1 secretion; this intercellular signaling relationship is an important component in the hepatic responses to endotoxin exposure.
Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas 78284-7760, USA.
A T
AT
Eakes
M S
MS
Olson
D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism*; D004731:Endotoxins / Q000494:pharmacology; D005786:Gene Expression Regulation; D007728:Kupffer Cells / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000098:blood supply*; D008297:Male; D010972:Platelet Activating Factor / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D017077:Culture Media, Conditioned; D019332:Endothelin-1; D004731:Endotoxins; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha