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Mast Cell IL-6 Improves Survival from Klebsiella Pneumonia and Sepsis by Enhancing Neutrophil Killing¹

Department of Medicine and The Cardiovascular Research Institute, University of California, San Francisco, CA 94143

The pleiotropic cytokine IL-6 has favorable and harmful effects on survival from bacterial infections. Although many innate immune cells produce IL-6, little is known about relevant sources in vivo and the nature of its contributions to host responses to severe bacterial infections. To examine these roles, we subjected mast cell-specific IL-6-deficient mice to the cecal ligation and puncture model of septic peritonitis, finding that survival in these mice is markedly worse than in controls. Following intranasal or i.p. inoculation with Klebsiella pneumoniae, IL-6 ^–/– mice are less likely to survive than wild-type controls and at the time of death have higher numbers of bacteria but not inflammatory cells in lungs and peritoneum. Similarly, mast cell-specific IL-6-deficient mice have diminished survival and higher numbers of K. pneumoniae following i.p. infection. Neutrophils lacking IL-6 have greater numbers of live intracellular K. pneumonia, suggesting impaired intracellular killing contributes to reduced clearance in IL-6^–/– mice. These results establish that mast cell IL-6 is a critical mediator of survival following K. pneumoniae infection and sepsis and suggest that IL-6 protects from death by augmenting neutrophil killing of bacteria.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant HL075026.

² R.E.S. and J.S.O. contributed equally to the study.

³ Address correspondence and reprint requests to Dr. Paul J. Wolters, Department of Medicine, University of California, San Francisco, Box 0111, San Francisco, CA 94143-111. E-mail address: paul.wolters{at}ucsf.edu

⁴ Abbreviations used in this paper: DPPI, dipeptidyl peptidase I; BMMC, bone marrow mast cell; CLP, cecal ligation and puncture; rm, recombinant mouse; SCF, stem cell factor.