Cholesterol 25-hydroxylase production by dendritic cells and macrophages is regulated by type I interferons.
The oxysterol-producing enzyme CH25H plays an important role in regulating lipid metabolism, gene expression, and immune activation. In vitro experiments using a panel of TLR agonists to activate BMDCs and macrophages demonstrated that Ch25h expression is induced rapidly, selectively, and robustly by the TLR ligands poly I:C and LPS. The mechanism of TLR3- and TLR4-induced transcription levels of Ch25h relies on the TRIF-mediated production of type I IFNs and requires signaling through the IFNαR and JAK/STAT1 pathway. Treatment of BMDCs and macrophages with IFN-α or IFN-β induces Ch25h in a STAT1-dependent manner. IFN-γ also up-regulated Ch25h expression by signaling through STAT1, suggesting that multiple pathways regulate the production of this enzyme. In addition, we demonstrated that regulation of Ch25h expression in vivo in lung-derived DCs and macrophages is dependent on signaling through the IFNαR and STAT1. The results suggest that the rapid induction of Ch25h and subsequent oxysterol synthesis may represent a component of the regulatory network that modulates the magnitude of innate immune reactions and possibly the nature and intensity of subsequent adaptive responses.
Park
Kiwon
K
The W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Scott
Alan L
AL
D000818:Animals; D003713:Dendritic Cells / Q000378:metabolism*; D007370:Interferon Type I / Q000502:physiology*; D053612:Janus Kinases / Q000502:physiology; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D057093:Orphan Nuclear Receptors / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000502:physiology; D015398:Signal Transduction; D013250:Steroid Hydroxylases / Q000096:biosynthesis*; D051193:Toll-Like Receptors / Q000502:physiology
D007370:Interferon Type I; D000071518:Liver X Receptors; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D057093:Orphan Nuclear Receptors; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D051193:Toll-Like Receptors; D013250:Steroid Hydroxylases; C507384:cholesterol 25-hydroxylase; D053612:Janus Kinases