A pivotal role of IL-12 in T^h1-dependent mouse liver injury

Abstract

Intravenous injection of Propionibacterium acnes and lipopolysaccharide (LPS) with a 7 day interval caused CD4+ T cell-dependent severe liver injury in the C57BL/6 (H-2b) mouse strain. In contrast, BALB/c (H-2d) mice were resistant to P. acnes and LPS-induced liver injury. The different susceptibilities of the two mouse strains to liver injury appeared to be closely correlated with their different abilities to produce IFN-gamma after P. acnes priming. Namely, the sensitive C57BL/6 mouse strain produced a significant level of IFN-gamma 7-10 days after P. acnes injection, whereas no significant amount of serum IFN-gamma was detected in the resistant BALB/c mouse strain. The important role of IFN-gamma in liver injury was demonstrated from the finding that in vivo administration of anti-IFN-gamma mAb abrogated P. acnes and LPS-induced liver injury in C57BL/6 mice. Moreover, it was demonstrated that in vivo administration of recombinant IL-12, a key cytokine for the induction of IFN-gamma, into mice induced P. acnes and LPS-induced liver injury in the resistant BALB/c mouse strain. Conversely, in vivo administration of anti-IL-12 mAb blocked the development of liver injury in the sensitive C57BL/6 mouse strain. Moreover, it was demonstrated that the failure of the induction of liver injury in BALB/c mice appeared to be derived from the lack of expression of IL-12 at the local site of liver in P. acnes-primed mice. These results strongly indicated that endogenous IL-12, which stimulates Th1-dominant cellular immunity and IFN-gamma production, may be an essential cytokine on the course of T cell-dependent liver injury.

Activating Immunity in the Liver. I. Liver Dendritic Cells (but Not Hepatocytes) Are Potent Activators of IFN-γ Release by Liver NKT Cells

“…We show in this paper that hepatocyte stimulation can result in IFN-␥ release of NKT cells when paracrine IL-12 is provided. IL-12 plays a pivotal role in Th1-dependent mouse liver injury (42). These data support the notion that DC but not hepatocytes are the critical initial trigger for the IFN-␥-dependent liver injury response.…”

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

“…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. Treatment with NE in ob/ob mice restores hepatic NKT cell population, reverses proinflammatory polarization, and significantly reduces hepatic inflammation.…”

Deletion of the Ron receptor tyrosine kinase domain in mice provides protection from endotoxin-induced acute liver failure

“…For example, deficiency in IFN-␥, IL-12, or IL-18 signaling leads to protection against LPSor TNF-␣-induced liver damage in mice 17,30,31 ; IFN-␥, in addition to having direct toxic effects on hepatocytes, may sensitize liver cells to the cytotoxicity of TNF-␣. [31][32][33] Alternatively, injection of IL-10, IL-1␤, or NO donors can protect murine liver from LPS/GalN-or TNF-␣/ GalN-induced hepatocyte apoptosis.…”