title: Interleukin-18 and interleukin-12 together downregulate ATP-binding cassette transporter A1 expression through the interleukin-18R/nuclear factor-κB signaling pathway in THP-1 macrophage-derived foam cells.
abstract: BACKGROUND
  Interleukin (IL)-18 and IL-12 synergize for the production of interferon (IFN)-γ, which can downregulate ATP-binding cassette transporter A1 (ABCA1) expression. The aim of the present study was to investigate the effect of IL-18 and/or IL-12 on ABCA1 expression.
  
  
  RESULTS
  IL-18 combined with IL-12 decreased ABCA1 expression and cellular cholesterol efflux in THP-1 macrophage-derived foam cells, whereas IL-18 or IL-12 alone had no effect. IL-12 increased IL-18 receptor (IL-18R) expression, which was suppressed by small interfering RNA (siRNA) for signal transducer and activator of transcription 3. IL-18R but not IL-12 receptor siRNA completely reversed the effects of IL-18 and IL-12 on ABCA1 expression and cellular cholesterol efflux. Treatment with IL-18 plus IL-12 markedly augmented nuclear translocation of nuclear factor (NF)-κB but had no effect on expression and activity of liver X receptor α. IL-18 and IL-12 also significantly increased zinc finger protein 202 (ZNF202) levels and IFN-γ secretion. Furthermore, siRNA for ZNF202 or IFN-γ significantly impaired IL-18/IL-12-induced suppression of ABCA1, whereas NF-κB siRNA treatment blocked IL-18/IL-12' action on ZNF202 levels, IFN-γ secretion, and ABCA1 expression.
  
  
  CONCLUSIONS
  IL-18 and IL-12 together can decrease ABCA1 expression and cellular cholesterol efflux in THP-1 macrophage-derived foam cells through the IL-18R/NF-κB signaling pathway.
authors.affiliation: Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, Hunan, China.
authors.forename: Xiao-Hua
authors.initials: XH
authors.lastname: Yu
authors.forename: Hai-Lu
authors.initials: HL
authors.lastname: Jiang
authors.forename: Wu-Jun
authors.initials: WJ
authors.lastname: Chen
authors.forename: Kai
authors.initials: K
authors.lastname: Yin
authors.forename: Guo-Jun
authors.initials: GJ
authors.lastname: Zhao
authors.forename: Zhong-Cheng
authors.initials: ZC
authors.lastname: Mo
authors.forename: Xin-Ping
authors.initials: XP
authors.lastname: Ouyang
authors.forename: Yun-Cheng
authors.initials: YC
authors.lastname: Lv
authors.forename: Zhi-Sheng
authors.initials: ZS
authors.lastname: Jiang
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Zhang
authors.forename: Chao-Ke
authors.initials: CK
authors.lastname: Tang
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D015536:Down-Regulation; D005487:Foam Cells / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D053707:Receptors, Interleukin-12 / Q000378:metabolism; D053724:Receptors, Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D020382:Interleukin-18; D000071518:Liver X Receptors; D016328:NF-kappa B; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C115745:ZNF202 protein, human; D018664:Interleukin-12; D007371:Interferon-gamma; D002784:Cholesterol