TLR2 and TLR4 agonists induce production of the vasoactive peptide endothelin-1 by human dendritic cells

• Published in: Molecular immunology 2009-09, Vol.46 (15), p.3178-3182
• Main Authors: Spirig, Rolf, Potapova, Inga, Shaw-Boden, Jane, Tsui, Janice, Rieben, Robert, Shaw, Sidney G.
• Format: Article
• Language: English
• Subjects: Cholecalciferol - analogs & derivatives; Cholecalciferol - pharmacology; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dexamethasone - pharmacology; Dinoprostone - pharmacology; Disulfides - pharmacology; Endothelin-1; Endothelin-1 - agonists; Endothelin-1 - antagonists & inhibitors; Endothelin-1 - biosynthesis; Glucocorticoids - pharmacology; Human; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit - immunology; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunity, Innate; Indole Alkaloids - pharmacology; Inflammation; Lipopolysaccharides - immunology; Oxytocics - pharmacology; Toll-like receptor; Toll-Like Receptor 2 - agonists; Toll-Like Receptor 4 - agonists; Vitamins - pharmacology
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2009.05.179

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, ETA and ETB, 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 1α,25-dihydroxyvitamin D3 results in a marked potentiation of the endothelin response, whereas prostaglandin E2 or dexamethasone do not increase ET-1 production. Furthermore, chetomin, an inhibitor of the transcription factor hypoxia-inducible factor 1α (HIF-1α), 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.