Redundant roles for cJun-N-terminal kinase 1 and 2 in interleukin-1β-mediated reduction and modification of murine hepatic nuclear retinoid X receptor α☆

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 1h 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.

Keywords: Liver, RXRα, JNK, IL-1β, Inflammation

Abbreviations: IL-1β, interleukin-1β, JNK, cJun-N-terminal kinase, LPS, lipopolysaccharide, RXR, retinoid X receptor