Effects of endotoxin tolerance on Propionibacterium acnes-primed lipopolysaccharide hepatic injury.
BACKGROUND
Prior administration of the Gram-positive bacteria Propionibacterium acnes (PA) results in hypersensitivity and hepatocyte necrosis to a subsequent low dose of lipopolysaccharide (LPS). Endotoxin tolerance has been shown to prevent lethality after ischemia/reperfusion injuries, sepsis, and endotoxic shock. We investigated whether prior induction of LPS tolerance could prevent subsequent PA-priming and LPS-induced death. The levels of known effector cytokines possibly responsible for these changes were measured.


METHODS
C57BL/6 (B6) mice were given heat-killed PA (0.5 mg/mouse) followed 7 days later by LPS (20 microg/mouse). In parallel experiments, B6 mice were pretreated with a single 20 microg/mouse dose of LPS (lethal dose = 800 microg/mouse) 7 days prior to PA priming. Animal survival, liver and spleen weights, and histology were examined. Cytokine levels of the inflammatory cytokines interferon-alpha, tumor necrosis factor-gamma, interleukin (IL)-6, and IL-12 and the anti-inflammatory cytokines IL-4 and IL-10 were measured by enzyme-linked immunosorbent assay and by reverse-transcription polymerase chain reaction.


RESULTS
Hepatomegaly, splenomegaly, and hepatocyte necrosis with death developed in all PA-primed B6 mice challenged with LPS. However, 83% of B6 mice given a tolerizing dose of LPS prior to PA survived (P < 0.01) without any increase in liver or spleen weights and without histological evidence of necrosis. Markedly decreased in vivo and in vitro inflammatory (interferon-alpha, tumor necrosis factor-gamma, IL-6, and IL-12) cytokine levels corresponded with survival in the LPS-tolerant mice. Endotoxin tolerance and subsequent survival were also associated with an increase in anti-inflammatory (IL-4 and IL-10) mRNA expression.


CONCLUSIONS
Lethal PA-primed LPS-induced hepatic injury can be prevented by administering a tolerizing dose of LPS prior to PA-priming. LPS protects the liver by preventing hepatic mononuclear cellular infiltration, reducing the production of the toxic proinflammatory cytokines, and inducing the production of endogenous anti-inflammatory cytokines.
Margenthaler
Julie A
JA
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
Landeros
Keith
K
Kataoka
Masaaki
M
Eilers
Mark
M
Ku
Grace
G
Flye
M Wayne
MW
D000818:Animals; D016207:Cytokines / Q000097:blood / Q000235:genetics; D016908:Gram-Positive Bacterial Infections / Q000276:immunology* / Q000401:mortality* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008107:Liver Diseases / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011425:Propionibacterium acnes; D012333:RNA, Messenger / Q000032:analysis; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016019:Survival Analysis
D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger