title: Enhancement of neutrophil function by interleukin-18 therapy protects burn-injured mice from methicillin-resistant Staphylococcus aureus.
abstract: Methicillin-resistant Staphylococcus aureus (MRSA) infection is a grave concern in burn-injured patients. We investigated the efficacy of interleukin-18 (IL-18) treatment in postburn MRSA infection. Alternate-day injections of IL-18 into burn-injured C57BL/6 mice significantly increased their survival after MRSA infection and after methicillin-sensitive S. aureus infection. Although IL-18 treatment of burn-injured mice augmented natural IgM production before MRSA infection and gamma interferon (IFN-γ) production after MRSA infection, neither IgM nor IFN-γ significantly contributed to the improvement in mouse survival. IL-18 treatment increased/restored the serum tumor necrosis factor (TNF), IL-17, IL-23, granulocyte colony-stimulating factor (G-CSF), and macrophage inflammatory protein (MIP-2) levels, as well as the neutrophil count, after MRSA infection of burn-injured mice; it also improved impaired neutrophil functions, phagocytic activity, production of reactive oxygen species, and MRSA-killing activity. However, IL-18 treatment was ineffective against MRSA infection in both burn- and sham-injured neutropenic mice. Enhancement of neutrophil functions by IL-18 was also observed in vitro. Furthermore, when neutrophils from IL-18-treated burn-injured mice were adoptively transferred into nontreated burn-injured mice 2 days after MRSA challenge, survival of the recipient mice increased. NOD-SCID mice that have functionally intact neutrophils and macrophages (but not T, B, or NK cells) were substantially resistant to MRSA infection. IL-18 treatment increased the survival of NOD-SCID mice after burn injury and MRSA infection. An adoptive transfer of neutrophils using NOD-SCID mice also showed a beneficial effect of IL-18-activated neutrophils, similar to that seen in C57BL/6 mice. Thus, although neutrophil functions were impaired in burn-injured mice, IL-18 therapy markedly activated neutrophil functions, thereby increasing survival from postburn MRSA infection.
authors.affiliation: Department of Microbiology, National Defense Medical College, Namiki 3-2, Tokorozawa 359-8513, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Hiromi
authors.initials: H
authors.lastname: Miyazaki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ono
authors.forename: Akihito
authors.initials: A
authors.lastname: Inatsu
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakashima
authors.forename: Hironori
authors.initials: H
authors.lastname: Tsujimoto
authors.forename: Nariyoshi
authors.initials: N
authors.lastname: Shinomiya
authors.forename: Daizoh
authors.initials: D
authors.lastname: Saitoh
authors.forename: Shuhji
authors.initials: S
authors.lastname: Seki
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002056:Burns / Q000276:immunology / Q000382:microbiology*; D016207:Cytokines / Q000097:blood; D007075:Immunoglobulin M / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D020382:Interleukin-18 / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000276:immunology* / Q000472:pathogenicity; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009504:Neutrophils / Q000276:immunology*; D010587:Phagocytosis / Q000187:drug effects; D013207:Staphylococcal Skin Infections / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology
chemical_list: D016207:Cytokines; D007075:Immunoglobulin M; D020382:Interleukin-18; D007371:Interferon-gamma