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Nat Med. 2007 Aug;13(8):927-34. Epub 2007 Jul 22.

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

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1
Department of Immunology and Cell Biology, Research Center Borstel, Parkallee 22, 23845 Borstel, Germany.

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.

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PMID:
17643110
DOI:
10.1038/nm1615
[Indexed for MEDLINE]

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