A role for IRF3-dependent RXRalpha repression in hepatotoxicity associated with viral infections.
Viral infections and antiviral responses have been linked to several metabolic diseases, including Reye's syndrome, which is aspirin-induced hepatotoxicity in the context of a viral infection. We identify an interferon regulatory factor 3 (IRF3)-dependent but type I interferon-independent pathway that strongly inhibits the expression of retinoid X receptor alpha (RXRalpha) and suppresses the induction of its downstream target genes, including those involved in hepatic detoxification. Activation of IRF3 by viral infection in vivo greatly enhances bile acid- and aspirin-induced hepatotoxicity. Our results provide a critical link between the innate immune response and host metabolism, identifying IRF3-mediated down-regulation of RXRalpha as a molecular mechanism for pathogen-associated metabolic diseases.
Chow
Edward K
EK
Molecular Biology Institute, Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Castrillo
Antonio
A
Shahangian
Arash
A
Pei
Liming
L
O'Connell
Ryan M
RM
Modlin
Robert L
RL
Tontonoz
Peter
P
Cheng
Genhong
G
D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D015967:Gene Expression Regulation, Viral / Q000276:immunology*; D006524:Hepatitis, Viral, Animal / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D047490:Retinoid X Receptor alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D012202:Reye Syndrome / Q000235:genetics / Q000276:immunology / Q000821:virology; D018353:Rhabdoviridae Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology
D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D047490:Retinoid X Receptor alpha