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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Acknowledgements
We thank R. Parker of the Biometrics Center of the Beth Israel Deaconess Medical Center for consultation regarding the statistical analysis of the data, S. Fish, L. Fox, M. Liebersbach and A. Xu for technical assistance, M.-H. Jouvin for discussions and critical reading of the manuscript, and R. Paus for supporting M. Metz. This work was supported by United States Public Health Science Grants (to S.J.G.), by grants of the Deutsche Forschungsgemeinschaft (to M. Maurer, J.W. and M. Metz), and by a grant of the Boehringer Ingelheim Fonds (to M. Metz).
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Supplementary information
Supplementary Figure 1
ET-1, but not a scrambled peptide, induces hypothermia in mast cell-deficient KitW/KitW-v mice. (PDF 17 kb)
Supplementary Figure 2
Co-incubation with mast cells ex vivo reduces the toxicity of ET-1 in vivo. (PDF 18 kb)
Supplementary Figure 3
Mast cells degrade ET-1 in vitro in a time- and dose-dependent manner. (PDF 40 kb)
Supplementary Figure 4
ET-1 induced degranulation. (PDF 52 kb)
Supplementary Figure 5
Pharmacological evidence that the ability of peritoneal mast cells to reduce the toxicity of ET-1 reflects their expression of ETA. (PDF 23 kb)
Supplementary Figure 6
Extent of PMC degranulation in Kit+/+ mice. (PDF 10 kb)
Supplementary Figure 7
In aperitoneal levels of endogenous ET-1 in female Kit+/+ mice.tr (PDF 11 kb)
Supplementary Figure 8
Pharmacological evidence that ET-1 contributes to mortality after CLP via ETB. (PDF 18 kb)
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Maurer, M., Wedemeyer, J., Metz, M. et al. Mast cells promote homeostasis by limiting endothelin-1-induced toxicity. Nature 432, 512–516 (2004). https://doi.org/10.1038/nature03085
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DOI: https://doi.org/10.1038/nature03085
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