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Adverse functions of IL-17A in experimental sepsis

Michael A. Flierl^*,1, Daniel Rittirsch^*,1, Hongwei Gao^,1, Laszlo M. Hoesel^*, Brian A. Nadeau^*, Danielle E. Day^*, Firas S. Zetoune^*, J. Vidya Sarma^*, Markus S. Huber-Lang, James L. M. Ferrara and Peter A. Ward^*,2

^* Department of Pathology, and

Departments of Pediatrics and Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA;

Department of Biochemistry and Molecular Biology, University of North Dakota Medical School, Grand Forks, North Dakota, USA; and

Department of Traumatology, Hand- and Reconstructive Surgery, University of Ulm Medical School, Ulm, Germany

²Correspondence: Department of Pathology, The University of Michigan Medical School, 1301 Catherine Rd., Ann Arbor, MI 48109-0602, USA. E-mail: pward{at}umich.edu

IL-17A is a proinflammatory cytokine produced by a variety of cells. In the current study, we examined the role of IL-17A in sepsis induced in mice by cecal ligation and puncture (CLP). IL-17A levels, which rose time-dependently in plasma after CLP, were not affected in the absence of β T cells or neutrophils. In sharp contrast, T cell-knockout or T cell-depleted mice displayed baseline IL-17A plasma levels after CLP. Neutralization of IL-17A by two different antibodies improved sepsis (survival from 10% to nearly 60%). Unexpectedly, antibody treatment was protective, even when administration of anti-IL-17A was delayed for up to 12 h after CLP. These protective effects of IL-17A blockade were associated with substantially reduced levels of bacteremia together with significant reductions of systemic proinflammatory cytokines and chemokines in plasma. In vitro incubation of mouse peritoneal macrophages with lipopolysaccharide (LPS) in the copresence of IL-17A substantially increased the production of TNF-, IL-1β, and IL-6 by these cells. These data suggest that, during experimental sepsis, T cell-derived IL-17A promotes high levels of proinflammatory mediators and bacteremia, resulting in enhanced lethality. IL-17A may be a potential therapeutic target in sepsis.—Flierl, M. A., Rittirsch, D., Gao, H., Hoesel, L. M., Nadeau, B. A., Day, D. E., Zetoune, F. S., Sarma, J. V., Huber-Lang, M. S., Ferrara, J. L. M., Ward, P. A. Adverse functions of IL-17A in experimental sepsis.

Key Words: • T cells • survival • colony-forming units • cytokines • chemokines

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