Murine macrophages produce endothelin-1 after microbial stimulation.
Endothelin-1 (ET-1) was originally characterized as a potent vasoconstrictor secreted by the endothelium and participating in the regulation of vascular tone. Subsequent analysis has revealed ET-1 to be a multifunctional peptide produced by a wide variety of cells and tissues under normal and pathologic conditions. The importance of macrophages as a source of ET-1 during infection and inflammation is supported by clinical observations in humans and in animal models of inflammation. We hypothesize that the production of ET-1 is part of the characteristic macrophage response to infection, and have begun to investigate the ability of various classes of microbes or microbial products to induce macrophage ET-1 production. We report the production of ET-1 by murine macrophages in response to stimulation with both gram-positive and gram-negative bacteria. Stimulation of macrophages with yeast (Candida albicans or Saccharomyces cerevisiae) or the protozoan parasite Leishmania major, elicited no significant release of ET-1. The production of ET-1 in response to lipopolysaccharide (LPS) was dose and time dependent, and required the expression of a functional toll-like receptor 4 (TLR4). Pharmacologic inhibition of the transcription factor, nuclear factor-kappaB (NF-kappaB) suppressed LPS-induced ET-1 production. Our findings complement the growing body of literature implicating a role for macrophage-derived ET-1 in inflammatory pathologies. The production of ET-1 by macrophages during infection and inflammation has the potential to affect tissue perfusion, leukocyte extravasation, and immune cell function.
Wahl
Jeffrey R
JR
Department of Microbiology, Des Moines University, College of Osteopathic Medicine, Des Moines, Iowa 50312, USA.
Goetsch
Nicholas J
NJ
Young
Heather J
HJ
Van Maanen
Ryan J
RJ
Johnson
Jason D
JD
Pea
Anisa S
AS
Brittingham
Andrew
A
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D017931:DNA Primers; D019332:Endothelin-1; D016328:NF-kappa B; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4