Adverse functions of IL-17A in experimental sepsis.
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 alphabeta T cells or neutrophils. In sharp contrast, gammadelta T cell-knockout or gammadelta T cell-depleted mice displayed baseline IL-17A plasma levels after CLP. Neutralization of IL-17A by two different antibodies improved sepsis (survival from approximately 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-alpha, IL-1beta, and IL-6 by these cells. These data suggest that, during experimental sepsis, gammadelta 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
Michael A
MA
Department of Pathology, The University of Michigan Medical School, 1301 Catherine Rd., Ann Arbor, MI 48109-0602, USA.
Rittirsch
Daniel
D
Gao
Hongwei
H
Hoesel
Laszlo M
LM
Nadeau
Brian A
BA
Day
Danielle E
DE
Zetoune
Firas S
FS
Sarma
J Vidya
JV
Huber-Lang
Markus S
MS
Ferrara
James L M
JL
Ward
Peter A
PA
D000818:Animals; D016470:Bacteremia; D002432:Cecum / Q000473:pathology; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D007249:Inflammation; D020381:Interleukin-17 / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011677:Punctures; D018805:Sepsis / Q000209:etiology / Q000503:physiopathology*; D013601:T-Lymphocytes / Q000473:pathology
D018925:Chemokines; D016207:Cytokines; D020381:Interleukin-17