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IL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities.

Abstract：

:Sepsis remains a global clinical problem. By using the mouse cecal ligation and puncture model of sepsis, here we identify an important aspect of mast cell (MC)-dependent, innate immune defenses against Gram-negative bacteria by demonstrating that MC protease activity is regulated by interleukin-15 (IL-15). Mouse MCs express both constitutive and lipopolysaccharide-inducible IL-15 and store it intracellularly. Deletion of Il15 in mice markedly increases chymase activities, leading to greater MC bactericidal responses, increased processing and activation of neutrophil-recruiting chemokines, and significantly higher survival rates of mice after septic peritonitis. By showing that intracellular IL-15 acts as a specific negative transcriptional regulator of a mouse MC chymase (mast cell protease-2), we provide evidence that defined MC protease activity is transcriptionally regulated by an intracellularly retained cytokine. Our results identify an unexpected breach in MC-dependent innate immune defenses against sepsis and suggest that inhibiting intracellular IL-15 in MCs may improve survival from sepsis.

journal_name

Nat Med

journal_title

Nature medicine

authors

Orinska Z,Maurer M,Mirghomizadeh F,Bulanova E,Metz M,Nashkevich N,Schiemann F,Schulmistrat J,Budagian V,Giron-Michel J,Brandt E,Paus R,Bulfone-Paus S

doi

10.1038/nm1615

subject

Has Abstract

pub_date

2007-08-01 00:00:00

pages

927-34

issue

8

eissn

1078-8956

issn

1546-170X

pii

nm1615

journal_volume

13

pub_type

杂志文章

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