Interleukin-15 induces IL-12 receptor beta1 gene expression through PU.1 and IRF 3 by targeting chromatin remodeling.
Interleukin-12 receptor beta1 (IL12RB1) is expressed on a variety of immune cells, including T and natural killer (NK) cells and macrophages, and is involved in innate and adaptive immune responses. Levels of IL12RB1 mRNA are dynamically regulated by various cytokines, including interferon-gamma (IFN-gamma) and IL-15. To reveal the regulatory mechanisms governing IL12RB1 gene expression, we analyzed the transcriptional regulatory region of the mouse IL12RB1 gene. Promoter analyses in a mouse macrophage cell line, RAW264.7, revealed that the 2508-bp region upstream of the transcriptional start site is sufficient for the full transcriptional activation of the IL12RB1 gene by IFN-gamma or IL-15. Analyses of the deletion mutants revealed critical roles of IRE/ISRE and ETS/PU.1 elements, to which IRF3 and PU.1, respectively, bound. Notably, chromatin immunoprecipitation (ChIP) assays revealed IL-15 rapidly induced histone H3 acetylation at the IL12RB1 promoter. Consistently, IL-15, as a histone deacetylase inhibitor, synergistically enhanced IL12RB1 gene expression and promoter activation by IFN-gamma through increased protein binding to ETS/PU.1 and IRE/ISRE sites. Additionally, IL12RB1 promoter activation by IFN-gamma was enhanced by the coexpression of a coactivator protein, CBP. Thus, IL-15 induces chromatin remodeling of the IL12RB1 gene promoter, increasing IL12RB1 mRNA expression in synergy with IFN-gamma through the recruitment of PU.1 and IRF3.
Musikacharoen
Tipayaratn
T
Division of Biochemistry and Molecular Dentistry, Department of Developmental Medicine, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Oguma
Asako
A
Yoshikai
Yasunobu
Y
Chiba
Norika
N
Masuda
Akio
A
Matsuguchi
Tetsuya
T
D020121:5' Untranslated Regions / Q000235:genetics; D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002843:Chromatin / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006657:Histones / Q000378:metabolism; D050838:Interferon Regulatory Factor-3; D007371:Interferon-gamma / Q000494:pharmacology; D019409:Interleukin-15 / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000235:genetics*; D053707:Receptors, Interleukin-12; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D020121:5' Untranslated Regions; D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D050838:Interferon Regulatory Factor-3; D007371:Interferon-gamma; D019409:Interleukin-15; D011518:Proto-Oncogene Proteins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D015534:Trans-Activators; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D000099232:Proto-Oncogene Protein Spi-1; C508440:Il12rb1 protein, mouse; C494233:Irf3 protein, mouse