In vivo IL-18 supplementation ameliorates lethal acute lung injury in burn-primed endotoxemic mice: a novel anti-inflammatory role of IL-18.
Previously, we have found that a prior burn insult induces lethal acute lung injury (ALI) and overproduction of proinflammatory cytokines after LPS challenge in mice. The current study was aimed to determine the role of IL-18 in burn-induced LPS hypersensitivity. Except sham group, mice were subjected to a 15% total body surface area full-thickness burn and either untreated or treated with IL-18 alone, IL-18 + anti-IL-10 antibody or IL-18 + isotype immunoglobulin G. LPS was intravenously administered to all mice on the 11th day, and the mice were killed at the indicated time point, or survival was examined. We additionally examined cytokine production by splenic cells in vitro for the elucidation of immunologic mechanisms. Unexpectedly, the liver IL-18 decreased transiently after burn injury, and in vivo IL-18 supplementation improved survival and ameliorated ALI, as well as reducing the lung contents of all cytokines examined, except IL-10. Neutralization of IL-10 cancelled the protective effect of IL-18. In splenic macrophages obtained from burned mice, the production of macrophage inflammatory protein 2 (MIP-2), TNF-alpha, and IL-10 was augmented, whereas in vivo IL-18 supplementation decreased MIP-2 production, but increased IL-10 production. Furthermore, a physiological concentration of IL-18 directly attenuated MIP-2 production by splenic cells in vitro. Burn injury induces LPS hypersensitivity through augmented production of proinflammatory cytokines by systemic macrophages. IL-18 supplementation is protective for LPS-induced lethal ALI through the direct anti-inflammatory effect on macrophages as well as by in vivo acceleration of IL-10 production, and could thus be an effective prophylactic strategy against septic complications in critically ill patients.
Sekine
Kazuhiko
K
Department of Emergency and Critical Care Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Fujishima
Seitaro
S
Sasaki
Junichi
J
Ishizaka
Akitoshi
A
Aiso
Sadakazu
S
Aikawa
Naoki
N
D055371:Acute Lung Injury / Q000503:physiopathology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use; D002056:Burns / Q000378:metabolism / Q000503:physiopathology*; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D019446:Endotoxemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D004797:Enzyme-Linked Immunosorbent Assay; D007074:Immunoglobulin G / Q000627:therapeutic use; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000906:Antibodies; D054426:Chemokine CXCL2; D007074:Immunoglobulin G; D020382:Interleukin-18; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10