title: 25-Hydroxycholesterol acts as an amplifier of inflammatory signaling.
abstract: Cross-talk between sterol regulatory pathways and inflammatory pathways has been demonstrated to significantly impact the development of both atherosclerosis and infectious disease. The oxysterol 25-hydroxycholesterol (25HC) plays multiple roles in lipid biosynthesis and immunity. We recently used a systems biology approach to identify 25HC as an innate immune mediator that had a predicted role in atherosclerosis and we demonstrated a role for 25HC in foam cell formation. Here, we show that this mediator also has several complex roles in the antiviral response. The host response to viruses involves gene regulatory circuits with multiple feedback loops and we show here that 25HC acts as an amplifier of inflammatory signaling in macrophages. We determined that 25HC amplifies inflammatory signaling, at least in part, by mediating the recruitment of the AP-1 components FBJ osteosarcoma oncogene (FOS) and jun proto-oncogene (JUN) to the promoters of a subset of Toll-like receptor-responsive genes. Consistent with previous reports, we found that 25HC inhibits in vitro infection of airway epithelial cells by influenza. Surprisingly, we found that deletion of Ch25h, the gene encoding the enzyme responsible for 25HC production, is protective in a mouse model of influenza infection as a result of decreased inflammatory-induced pathology. Thus, our study demonstrates, for the first time to our knowledge, that in addition to its direct antiviral role, 25HC also regulates transcriptional responses and acts as an amplifier of inflammation via AP-1 and that the resulting alteration in inflammatory response leads to increased tissue damage in mice following infection with influenza.
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA 98109; and alan.aderem@seattlebiomed.org.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Gold
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA 98109; and.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Diercks
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA 98109; and.
authors.forename: Irina
authors.initials: I
authors.lastname: Podolsky
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA 98109; and.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Podyminogin
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA 98109; and.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Askovich
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, WA 98195.
authors.forename: Piper M
authors.initials: PM
authors.lastname: Treuting
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA 98109; and alan.aderem@seattlebiomed.org.
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D025461:Feedback, Physiological / Q000187:drug effects; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D007251:Influenza, Human / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000378:metabolism / Q000473:pathology; D011070:Poly I-C / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D015398:Signal Transduction / Q000187:drug effects*; D013250:Steroid Hydroxylases / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D006888:Hydroxycholesterols; D000071518:Liver X Receptors; C000715470:MAS1 protein, human; D057093:Orphan Nuclear Receptors; D000090063:Proto-Oncogene Mas; D018808:Transcription Factor AP-1; C007997:25-hydroxycholesterol; D013250:Steroid Hydroxylases; C507384:cholesterol 25-hydroxylase; D011070:Poly I-C