1. Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA
2. Department of Dermatology, Universität Mainz, D-55101 Mainz, Germany
3. Department of Dermatology and Allergy, University Hospital Charité, Humboldt University Berlin, D-10117, Germany
4. Department of Pathology, Stanford University School of Medicine, Stanford, California 94305-5324, USA
5. Department of Gastroenterology, Hepatology and Endocrinology, Center of Internal Medicine, Medizinische Hochschule Hannover, 30623 Hannover, Germany
6. Department of Molecular, Cellular and Craniofacial Biology, University of Louisville, Louisville, Kentucky 40292, USA
7. Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9050, USA
8. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9050, USA
9. Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9050, USA
10. These authors contributed equally to this work

Correspondence to: Stephen J. Galli^1,4 Email: sgalli@stanford.edu.

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 processes^{2, 3}, including the vascular changes associated with sepsis^{2, 3, 4, 5}. However, the factors that regulate ET-1-associated toxicity during bacterial infections, or in other settings, are not fully understood^{2, 3, 4, 5}. Both the pathology associated with certain allergic and autoimmune disorders^{6, 7}, and optimal host defence against bacterial and parasitic infections^{8, 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 (ET_A)-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 ET_A-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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