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

Endothelin-1 (ET-1) is a 21-amino-acid peptide, derived from vascular endothelial cells, with potent vasoconstrictor activity(1). ET-1 has been implicated in diverse physiological or pathological processes(2,3), including the vascular changes associated with sepsis(2-5). However, the factors that regulate ET-1-associated toxicity during bacterial infections, or in other settings, are not fully understood(2-5). Both the pathology associated with certain allergic and autoimmune disorders(6,7), and optimal host defence against bacterial and parasitic infections(8-10) 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 activation(12,13), 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.