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. ET-1 has been implicated in diverse physiological or pathological processes, including the vascular changes associated with sepsis. However, the factors that regulate ET-1-associated toxicity during bacterial infections, or in other settings, are not fully understood. Both the pathology associated with certain allergic and autoimmune disorders, and optimal host defence against bacterial and parasitic infections 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, 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.
Maurer
Marcus
M
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Wedemeyer
Jochen
J
Metz
Martin
M
Piliponsky
Adrian M
AM
Weller
Karsten
K
Chatterjea
Devavani
D
Clouthier
David E
DE
Yanagisawa
Masashi M
MM
Tsai
Mindy
M
Galli
Stephen J
SJ
D000818:Animals; D001831:Body Temperature; D001835:Body Weight; D015550:Cell Degranulation / Q000187:drug effects; D002470:Cell Survival; D053818:Chymases; D003967:Diarrhea / Q000139:chemically induced; D064420:Drug-Related Side Effects and Adverse Reactions; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D019332:Endothelin-1 / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000633:toxicity*; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D007274:Injections, Intraperitoneal; D008407:Mast Cells / Q000166:cytology / Q000201:enzymology / Q000502:physiology* / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010538:Peritonitis / Q000503:physiopathology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology; D015996:Survival Rate
D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; C002101:chymostatin; D019009:Proto-Oncogene Proteins c-kit; D012697:Serine Endopeptidases; D053818:Chymases; C072247:cyclo(Trp-Asp-Pro-Val-Leu)