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ORIGINAL RESEARCH ARTICLE

Murine Macrophages Produce Endothelin-1 After Microbial Stimulation

Department of Microbiology, Des Moines University, College of Osteopathic Medicine, Des Moines, Iowa 50312

To whom requests for reprints should be addressed at ¹ Department of Microbiology, Des Moines University, College of Osteopathic Medicine, 3200 Grand Avenue, Des Moines, Iowa 50312. E-mail: Andrew.Brittingham{at}dmu.edu

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-B (NF-B) 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.

Key Words: macrophage • endothelin-1 • lipopolysaccharide • toll-like receptor 4

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