Redundant roles for cJun-N-terminal kinase 1 and 2 in interleukin-1beta-mediated reduction and modification of murine hepatic nuclear retinoid X receptor alpha.
OBJECTIVE
Retinoid X receptor alpha (RXRalpha), 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 RXRalpha levels downstream of interleukin-1beta (IL-1beta) in vivo.


METHODS
Effects of IL-1beta on hepatic NR-dependent gene expression, nuclear RXRalpha 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-1beta administration showed a time-dependent reduction in expression of the hepatic NR-dependent genes Ntcp, Cyp7a1, Cyp8b1, Abcg5, Mrp2, and Mrp3. IL-1beta treatment for 1h activated JNK and resulted in both post-translational modification and reduction of nuclear RXRalpha. In wild-type primary hepatocytes, IL-1beta modified and reduced nuclear RXRalpha 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 RXRalpha by IL-1beta both in vivo and in primary hepatocytes.


CONCLUSIONS
Functional redundancy exists for JNK1 and JNK2 in IL-1beta-mediated alterations of hepatic nuclear RXRalpha levels, stressing the importance of this pathway in mediating the hepatic response to inflammation.
Kosters
Astrid
A
Texas Children's Liver Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
White
Damara D
DD
Sun
Hongdan
H
Thevananther
Sundararajah
S
Karpen
Saul J
SJ
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha
D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D047490:Retinoid X Receptor alpha; D014409:Tumor Necrosis Factor-alpha; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8