TLR2 and TLR4 agonists induce production of the vasoactive peptide endothelin-1 by human dendritic cells.
Endothelin-1 (ET-1) is mainly secreted by endothelial cells and acts as a potent vasoconstrictor. In addition ET-1 has also been shown to have pleiotropic effects on a variety of other systems including adaptive immunity. There are two main ET-1 receptors, ET(A) and ET(B), which have different tissue and functional distributions. Dendritic cells (DC) are pivotal antigen-presenting cells linking the innate with the adaptive immune system. DC are sentinels expressing pattern-recognition receptors, e.g. the toll-like receptors (TLR) for detecting danger signals released from pathogens or tissue injury. Here we show for the first time that stimulation of human monocyte-derived DC with exogenous as well as endogenous selective TLR4 and TLR2 agonists induces the production of ET-1 in a dose- and time-dependent manner. 'Alternative' activation of DC in the presence of 1alpha,25-dihydroxyvitamin D(3) results in a marked potentiation of the endothelin response, whereas prostaglandin E(2) or dexamethasone do not increase ET-1 production. Furthermore, chetomin, an inhibitor of the transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha), prevents TLR-mediated secretion of ET-1. Surprisingly, stimulation of human monocytes with LPS does not lead to secretion of detectable amounts of ET-1. These results suggest a role of ET-1 as an important player in human DC biology and innate immunity in general.
Spirig
Rolf
R
Laboratory of Cardiovascular Research, Department of Clinical Research, University of Bern, Switzerland.
Potapova
Inga
I
Shaw-Boden
Jane
J
Tsui
Janice
J
Rieben
Robert
R
Shaw
Sidney G
SG
D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004220:Disulfides / Q000494:pharmacology; D019332:Endothelin-1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D007113:Immunity, Innate; D026121:Indole Alkaloids / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology; D010120:Oxytocics / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000819:agonists*; D051197:Toll-Like Receptor 4 / Q000819:agonists*; D014815:Vitamins / Q000494:pharmacology
D004220:Disulfides; D019332:Endothelin-1; D005938:Glucocorticoids; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D026121:Indole Alkaloids; D008070:Lipopolysaccharides; D010120:Oxytocics; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014815:Vitamins; C001598:chetomin; D002762:Cholecalciferol; D003907:Dexamethasone; D015232:Dinoprostone