Regulation of IL-27 p28 gene expression in macrophages through MyD88- and interferon-gamma-mediated pathways.
Interleukin (IL)-27 is the newest member of the IL-12 family of heterodimeric cytokines composed of the Epstein-Barr virus-induced gene 3 and p28 chains. IL-27 not only plays an important role in the regulation of differentiation of naive T helper cells but also possesses antiinflammatory properties. IL-27 is an early product of activated monocytes/macrophages and dendritic cells. However, the mechanisms whereby inflammatory signals stimulate IL-27 production have not been explored. In this study, we investigated the transcriptional regulation of the mouse IL-27 p28 gene in macrophages in response to lipopolysaccharide (LPS) and interferon (IFN)-gamma. We found that LPS-stimulated p28 production was completely dependent on the Toll-like receptor 4/myeloid differentiation factor 88 (MyD88)-mediated pathway but only partially dependent on nuclear factor kappaB c-Rel. IFN-gamma-induced p28 production/secretion was also partially dependent on MyD88 but independent of c-Rel. We then cloned the mouse p28 gene promoter and mapped its multiple transcription initiation sites. Furthermore, we identified critical promoter elements that mediate the inductive effects of LPS and IFN-gamma, separately and synergistically, on p28 gene transcription in a c-Rel- and interferon regulatory factor 1-dependent manner, respectively.
Liu
Jianguo
J
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Guan
Xiuqin
X
Ma
Xiaojing
X
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D050856:Interferon Regulatory Factor-1 / Q000172:deficiency / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D021122:Protein Subunits / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects
D018076:DNA, Complementary; C486767:Il27 protein, mouse; D050856:Interferon Regulatory Factor-1; D007378:Interleukins; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D021122:Protein Subunits; D012333:RNA, Messenger; D011994:Recombinant Proteins; D007371:Interferon-gamma