The resistance of P. acnes -primed interferon γ-deficient mice to low-dose lipopolysaccharide-induced acute liver injury

Abstract

Endotoxin has been identified as a principal mediator of sepsis, often with resulting multiple organ failure. Although interferon ␥ (IFN-␥) has a central role in controlling bacterial infection through the activation of macrophages and T lymphocytes, it can also enhance the harmful effects of the inflammatory response. To examine the role of IFN-␥ in lipopolysaccharide (LPS)-induced injury, we administered LPS (20 or 800 g/mouse) alone or as low-dose LPS (20 g/mouse) 7 days after heat-killed Propionibacterium acnes (P. acnes) injection into wild-type C57BL/6 (B6) mice or IFN-␥-deficient (GKO) mice (B6 background). Although low-dose (20 g) LPS alone had no effect on survival, the administration of 800 g LPS alone resulted in 100% mortality in both B6 and GKO mice without significant hepatic mononuclear cellular infiltration or differences in elevated plasma tumor necrosis factor ␣ (TNF-␣), interleukin 6 (IL-6), and IL-12 levels. In contrast, mortality after low-dose (20 g) LPS challenge in P. acnes-primed B6 mice was 100%, but 0% in GKO mice. In vivo plasma cytokine (IFN-␥, TNF-␣, IL-6, and IL-12) levels and in vitro cytokine production by hepatic mononuclear cells were significantly higher in B6 mice compared with GKO mice. Associated hepatic mononuclear cellular infiltration, multifocal liver necrosis, hepatomegaly, and splenomegaly were found in B6 mice, but not in GKO mice. Finally, the anti-inflammatory NK1.1؉CD4؉ cell proportion of hepatic infiltrating mononuclear cell numbers 7 days after P. acnes administration was significantly reduced in B6 compared with GKO mice, whereas the proportion of inflammatory NK1.1؉CD4؊ cells was increased. In conclusion, these data suggest that IFN-␥ mediates P. acnes-primed low-dose LPS injury through the hepatic infiltration of mononuclear cells and the subsequent elevation of inflammatory cytokines after LPS challenge, whereas the lethal effects of high-dose LPS alone does not depend on the presence of IFN-␥. (HEPATOLOGY 2002;35: 805-814.)

Selective priming to Toll-like receptor 4 (TLR4), not TLR2, ligands by P. acnes involves up-regulation of MD-2 in mice

“…27,28 A recent study suggested that IFN-␥ can prevent TLR4 homotolerance. 29 IFN-␥ is a key cytokine in P. acnes priming, 9 and we found it to be significantly elevated in the sera of P. acnes-primed animals (see Fig. 3A).…”

“…The mechanisms for induction of TLR4 and MD-2 by P. acnes seem to involve IFN-␥, a key mediator of liver sensitization by P. acnes. 6,9 More recently, IFN-␥ was shown to regulate expression of both MD-2 and TLR4 in intestinal epithelial cells. 33 Thus, the IFN-␥-responsive region identified in the promoter region of MD-2 that acts through the Janus tyrosine kinase-STAT pathway is a potential candidate to mediate this activation.…”

“…6 -8 P. acnes-induced sensitization is thought to be mediated by IFN-␥ and requires IL-12 and IL-18 activation. 6,9 The mechanisms whereby P. acnes and these mediators cause sensitization to LPS are only partially understood and may involve molecules associated with LPS recognition and signaling. LPS-mediated signaling requires assembly of the receptor complex that includes a homodimer of the recently identified Toll-like receptor 4 (TLR4) and its coreceptors, CD14 and MD-2.…”

Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis

“…24 However, IFN-␥ sensitization to TNF-␣ is also critically important, because mice that are genetically deficient in IFN-␥ are completely protected from LPS hepatotoxicity despite persistent TNF-␣ expression. 25 NKT cells produce both IFN-␥ and IL-4. 5 While the former exacerbates TNF-␣ toxicity, the latter is a key inducer of anti-inflammatory (Th-2) cytokines, which generally attenuate the toxic effects of TNF-␣.…”

“…For example, overabundance of proinflammatory cytokines such as IFN-␥ sensitizes hepatocytes to liver injury upon subsequent exposure to doses of LPS that are well-tolerated when IFN-␥ is not excessive. 25 NKT cell populations normally control proinflammatory Th-1 cytokine activities by promoting the production of anti-inflammatory Th-2 cytokines. 42 Thus, when proinflammatory cytokine activity is not tempered by anti-inflammatory cytokines, sustained Th-1 polarization, chronic inflammation, and progressive tissue injury ensue in response to stimuli that typically signal a self-limited inflammatory response.…”