Article abstract
Nature Medicine 13, 927 - 934 (2007)
Published online: 22 July 2007 | doi:10.1038/nm1615
IL-15 constrains mast cell–dependent antibacterial defenses by suppressing chymase activities
Zane Orinska1,6, Marcus Maurer2,6, Farhad Mirghomizadeh1,6, Elena Bulanova1, Martin Metz2,3, Natalia Nashkevich1, Florian Schiemann1, Jan Schulmistrat1, Vadim Budagian1, Julien Giron-Michel4, Ernst Brandt1, Ralf Paus5 & Silvia Bulfone-Paus1
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.
- Department of Immunology and Cell Biology, Research Center Borstel, Parkallee 22, 23845 Borstel, Germany.
- Department of Dermatology and Allergy, Allergie-Centrum-Charité, Charité–Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
- Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
- U542 Institut National de la Santé et de la Recherche Médical (INSERM), Hôpital Paul Brousse, 94807 Villejuif, France.
- Department of Dermatology, University Hospital Schleswig-Holstein, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
- These authors contributed equally to this work.
Correspondence to: Silvia Bulfone-Paus1 e-mail: sbulfone@fz-borstel.de
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsisNature Medicine Article (01 Apr 2008)
Mast cell production of IL-4 and TNF may be required for protective and pathological responses in gastrointestinal helminth infectionMucosal Immunology Article Response
Mast cell production of IL-4 and TNF may be required for protective and pathological responses in gastrointestinal helminth infectionMucosal Immunology Article Response
IL-15 constrains mast cell–dependent antibacterial defenses by suppressing chymase activities&showall=research" class="allmatches" target="_new">See all 11 matches for Research
