ABSTRACT:During inflammation, drug metabolism and clearance are altered due to suppression of hepatic drug-metabolizing enzyme (DME) genes and their regulatory nuclear receptors (NRs) [pregnane X receptor, constitutive androstane receptor, and retinoid X receptor ␣ (RXR␣)]. The bacterial endotoxin, lipopolysaccharide (LPS), induces expression of proinflammatory cytokines in the liver, which contribute to altered DME expression. LPS binds to the cell-surface receptor, Toll-like receptor 4 (TLR4), which initiates a signal transduction cascade, including recruitment of the Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP). However, the role of TLR4 and TIRAP in LPS-mediated regulation of hepatic DME gene expression is not known. Wild-type (C3HeB/FeJ), TLR4-mutant (C3H/HeJ), TIRAP ؉/؉ , and TIRAP ؊/؊ mice were injected i.p.with LPs. RNA levels of the major hepatic DME, Cyp3a11 and Ugt1a1, and the NRs were suppressed ϳ60 to 70% by LPS in wild-type but not in the TLR4-mutant mice. The nuclear protein levels of RXR␣ were reduced by LPS in wild-type but not in TLR4-mutant mice. Induction of hepatic cytokines (interleukin-1␤, tumor necrosis factor-␣, and interleukin-6), c-Jun N-terminal kinase, and nuclear factor-〉 was blocked in TLR4-mutant mice. Surprisingly, LPS had the same effect on cytokines, kinases, NRs, and DME genes in livers of both TIRAP

Background/Aims-Retinoid X receptor α (RXRα), the heterodimeric partner for multiple nuclear receptors (NRs), was shown to be an essential target for inflammation-induced cJun-N-terminal kinase (JNK) signaling in vitro. This study aimed to explore the role of hepatic JNK signaling and its effects on nuclear RXRα levels downstream of interleukin-1β (IL-1β) in vivo.Methods-Effects of IL-1β on hepatic NR-dependent gene expression, nuclear RXRα levels, and roles for individual JNK isoforms were studied in wild-type, Jnk1 −/− , and Jnk2 −/− mice and in primary hepatocytes of each genotype.Results-IL-1β administration showed a time-dependent reduction in expression of the hepatic NR-dependent genes Ntcp, Cyp7a1, Cyp8b1, Abcg5, Mrp2, and Mrp3. IL-1β treatment for 1 hour activated JNK and resulted in both post-translational modification and reduction of nuclear RXRα. In wild-type primary hepatocytes, IL-1β modified and reduced nuclear RXRα levels time dependently, which was prevented by chemical inhibition of JNK as well as by inhibition of proteasomal degradation. Individual absence of either JNK1 or JNK2 did not significantly influence the reduction or modification of hepatic nuclear RXRα by IL-1β both in vivo and in primary hepatocytes.Conclusions-Functional redundancy exists for JNK1 and JNK2 in IL-1β-mediated alterations of hepatic nuclear RXRα levels, stressing the importance of this pathway in mediating the hepatic response to inflammation.

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