Effects of endotoxin tolerance on Propionibacterium acnes-primed lipopolysaccharide hepatic injury

Julie A. Margenthaler, Keith Landeros, Masaaki Kataoka, Mark Eilers, Grace Ku, M. Wayne Flye

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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 μg/mouse). In parallel experiments, B6 mice were pretreated with a single 20 μg/mouse dose of LPS (lethal dose = 800 μg/mouse) 7 days prior to PA priming. Animal survival, liver and spleen weights, and histology were examined. Cytokine levels of the inflammatory cytokines interferon-α, tumor necrosis factor-γ, 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-α, tumor necrosis factor-γ, 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.

Original languageEnglish
Pages (from-to)102-110
Number of pages9
JournalJournal of Surgical Research
Issue number1
StatePublished - Jun 1 2003


  • Cytokines
  • Endotoxin
  • Hepatic mononuclear cells
  • P. acnes


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