title: Neutralization of IL-10 restores the downregulation of IL-18 receptor on natural killer cells and interferon-γ production in septic mice, thus leading to an improved survival.
abstract: The objective of the study was to investigate the mechanisms of insufficient interferon-γ (IFN-γ) response to interleukin 18 (IL-18) and the treatment for the insufficient response in septic mice. Interleukin 18 stimulation does not restore IFN-γ production by blood mononuclear cells in septic patients but does restore its production in postoperative patients. Although sepsis impairs the IFN-γ response to IL-18, little is known about why the IL-18/IFN-γ-mediated immune response is ineffective in patients with sepsis. A cecal ligation and puncture was made in C57BL/6 mice following a sublethal lipopolysaccharide challenge to examine their IFN-γ response to IL-18, focusing on natural killer (NK) cells and cytokines. We next examined the effect of neutralization of IL-10 on the NK cell and survival in septic mice. Interleukin 18 injection did not restore IFN-γ production in septic (cecal ligation and puncture) mice. Despite an increase in the numbers of liver NK cells, the IL-18 receptor (IL-18R) expression was decreased in the septic mice compared with sham mice. Serum IL-10 levels were positively correlated with the percentage of liver NK cells, but negatively with their IL-18R expression. Neutralization of IL-10 restored the IL-18R expression on liver NK cells and restored the IFN-γ response in the septic mice, improving their survival. Sepsis might impair IL-18R expression on liver and spleen NK cells and impair the IL-18-mediated IFN-γ response. Neutralization of IL-10 may restore this response in septic hosts, thereby improving survival.
authors.affiliation: Department of Surgery, National Defense Medical College, Saitama, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hiraki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ono
authors.forename: Manabu
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Hironori
authors.initials: H
authors.lastname: Tsujimoto
authors.forename: Risa
authors.initials: R
authors.lastname: Takahata
authors.forename: Hiromi
authors.initials: H
authors.lastname: Miyazaki
authors.forename: Daizoh
authors.initials: D
authors.lastname: Saitoh
authors.forename: Shuji
authors.initials: S
authors.lastname: Seki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hase
mesh_terms: D000818:Animals; D015536:Down-Regulation; D005434:Flow Cytometry / Q000379:methods; D007371:Interferon-gamma / Q000378:metabolism*; D016753:Interleukin-10 / Q000097:blood / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology*; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D053724:Receptors, Interleukin-18 / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D013154:Spleen / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D008070:Lipopolysaccharides; D053724:Receptors, Interleukin-18; D016753:Interleukin-10; D007371:Interferon-gamma