Interleukin-12 and -18 induce severe liver injury in mice recovered from peritonitis after sublethal endotoxin challenge.
BACKGROUND
Postoperative intraabdominal abscess is the major complication after abdominal surgery, and additional infection is often observed and becomes the leading cause of death in septic patients who survive initial resuscitation. Sepsis is initiated and perpetuated by the overzealous systemic production of proinflammatory cytokines-such as tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-12, and IL-18-sometimes resulting in excessive tissue injury and death. The purpose of this study was to assess the correlation between liver and spleen innate cytokine responses and organ dysfunction in sepsis syndrome.


METHODS
Peritonitis was induced by cecal ligation and puncture (CLP). All CLP mice survived more than 7 days after the procedure, and serum cytokine (TNF-alpha, IL-12, IL-18, and IL-10) levels peaked 12 hours after CLP; thereafter, they returned to basal levels 7 days after CLP. The mice were injected with a sublethal dose of lipopolysaccharide (LPS) 7 days after CLP. Survival rates, tissue damage, serum cytokine levels, and cytokine production of liver or spleen mononuclear cells (MNCs) were evaluated.


RESULTS
All CLP mice died within 6 hours from liver injury 7 days after LPS challenge, but all sham mice survived. IL-12, IL-18, and IFN-gamma levels in supernatants of the liver MNCs stimulated with LPS in CLP mice were significantly higher than those in sham mice 7 days after the procedure. Furthermore, serum IL-12 and IL-18 levels and liver MNCs IL-12, IL-18, and IFN-gamma production were significantly increased in CLP mice compared with sham mice after LPS challenge. Thereafter, effects of anti-IL-12 and/or anti-IL-18 antibody were evaluated in LPS-injected CLP mice. The survival rate of LPS-injected CLP mice treated with both anti-IL-12 and anti-IL-18 antibody was significantly better than that of untreated mice. Furthermore, liver damage was improved.


CONCLUSIONS
Mice recovered from mild peritonitis died of severe liver injury by subsequent injection of a sublethal dose of LPS, and this liver injury was related to the collaborating production of IL-12 and IL-18 by liver MNCs.
Ono
Satoshi
S
Department of Surgery I, National Defense Medical College, Saitama, Japan.
Ueno
Chikara
C
Seki
Shuhji
S
Matsumoto
Atsushi
A
Mochizuki
Hidetaka
H
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004926:Escherichia coli; D018664:Interleukin-12 / Q000378:metabolism / Q000502:physiology*; D020382:Interleukin-18 / Q000378:metabolism / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010538:Peritonitis / Q000378:metabolism / Q000473:pathology*; D018805:Sepsis / Q000378:metabolism / Q000473:pathology*; D013154:Spleen / Q000378:metabolism
D016207:Cytokines; D020382:Interleukin-18; D008070:Lipopolysaccharides; D018664:Interleukin-12