Tolerogenic role of Kupffer cells in allergic reactions.

Drug-induced allergic reactions (DIARs), including allergic hepatitis, cutaneous reactions, and blood dyscrasias, are unpredictable and can be life threatening. Although current studies suggest that DIARs are caused by immunogenic drug-protein adducts, it remains unclear what factors determine the susceptibility to DIARs. We hypothesized that most individuals may be resistant to DIARs in part because they become immunologically tolerant to drug-protein adducts in the liver, an organ with tolerogenic properties. Because animal models of DIARs are elusive, we tested this hypothesis using a murine model of 2,4-dinitrochlorobenzene (DNCB)-induced delayed type hypersensitivity reaction that is mediated by immunogenic 2,4-dinitrophenylated (DNP)-protein adducts. Intravenous pretreatment of mice with DNP-BSA led to its accumulation in hepatic Kupffer cells (KC) and induced immunological tolerance to subsequent DNCB sensitization. Tolerance could be abrogated by prior depletion of KC or induced in naïve mice by transferring a T cell-depleted, KC-enriched fraction of liver nonparenchymal cells from mice tolerized 1 month earlier by DNP-BSA pretreatment. These findings implicate KC as a primary and sustained inducer of tolerance against DNP-protein adducts and suggest a similar role in modulating allergic reactions against drug-protein adducts. Perhaps genetic and/or environmental factors affecting the activities of these cells may play a role in determining individual susceptibility to DIARs.

Role of interleukin-6 in hepatic heat shock protein expression and protection against acetaminophen-induced liver disease.

Recent experimental data suggest that the idiosyncratic nature of drug-induced liver disease (DILD) may be due in part to a deficiency of one or more hepatoprotective factors. In this study we have investigated whether interleukin (IL)-6 may also be one of these factors. Following the induction of liver injury with acetaminophen (APAP), a time-dependent increase in liver mRNA expression of IL-6 and its family members IL-11, leukemia inhibitory factor, and oncostatin M was observed in wild type (WT) mice, suggesting a possible hepatoprotective role played by this cytokine family. Indeed, mice lacking IL-6 (IL-6-/-) were more susceptible than were WT mice to APAP-induced liver injury. The increased susceptibility of the IL-6-/- mice was associated with a deficiency in the expression of hepatic heat shock protein (HSP)25, 32, and 40 as well as inducible HSP70 following APAP treatment. These results suggest that IL-6 and possibly other family members may protect the liver from injury, at least in part, by up-regulating the hepatic expression of several cytoprotective HSPs.