Mast cells promote homeostasis by limiting endothelin-1-induced toxicity

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Abstract
Endothelin-1 (ET-1) is a 21-amino-acid peptide, derived from vascular endothelial cells, with potent vasoconstrictor activity1. ET-1 has been implicated in diverse physiological or pathological processes2,3, including the vascular changes associated with sepsis2,3,4,5. However, the factors that regulate ET-1-associated toxicity during bacterial infections, or in other settings, are not fully understood2,3,4,5. Both the pathology associated with certain allergic and autoimmune disorders6,7, and optimal host defence against bacterial and parasitic infections8,9,10 are mediated by mast cells. In vitro, mast cells can produce ET-1 (ref. 11), undergo ET-1-dependent and endothelin-A receptor (ETA)-dependent activation12,13, and release proteases that degrade ET-1 (ref. 14). Although the potential relationships between mast cells and the ET-1 system thus may be complex, the importance of interactions between ET-1 and mast cells in vivo is obscure. Here we show that ETA-dependent mast-cell activation can diminish both ET-1 levels and ET-1-induced pathology in vivo, and also can contribute to optimal survival during acute bacterial peritonitis. These findings identify a new biological function for mast cells: promotion of homeostasis by limiting the toxicity associated with an endogenous mediator.

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