Activation of IL-27 p28 gene transcription by interferon regulatory factor 8 in cooperation with interferon regulatory factor 1.
Interferon regulatory factor (IRF) family members, especially interferon regulatory factor-1 (IRF-1) and interferon regulatory factor-8 (IRF-8 or ICSBP), play important roles in interferon signaling in a wide range of host responses to infection and tumor growth. Interleukin-27 (IL-27), as a member of the IL-12 cytokine family, not only acts as a proinflammatory cytokine that regulates the differentiation of naive T helper cells but also possesses anti-inflammatory properties. IL-27 consists of EBI3 (Epstein-Barr virus-induced gene 3) and p28 subunits. Our previous work has shown that IRF-1 regulates IL-27 p28 gene transcription by specifically binding to the IRF-1 response element in the p28 promoter. In this study, we found that IRF-8-deficient macrophages were highly defective in the production of IL-27 p28 at both mRNA and protein levels. Circulating IL-27 p28 in serum was also decreased in IRF-8(-/-) mice in a septic shock model. Lipopolysaccharide, as a potent inducer of IL-27 p28 expression, could activate IRF-8 expression in a MyD88-dependent pathway, which in turn induced p28 gene transcription through NF-kappaB and/or IRF-8. Transcriptional analyses revealed that IRF-8 activated p28 gene transcription through binding to a site located at -57 to -48 in the p28 promoter overlapping the IRF-1 binding site. Consistent with this observation, overexpression of both IRF-8 and IRF-1 additively activated IL-27 p28 promoter. This study provides further mechanistic information regarding how signals initiated during innate and adaptive immune responses synergize to yield greater IL-27 production and sustained cellular immunity.
Zhang
Jidong
J
Division of Immunobiology, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, Missouri 63104, USA.
Qian
Xuesong
X
Ning
Huan
H
Yang
Jianjun
J
Xiong
Huabao
H
Liu
Jianguo
J
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D007249:Inflammation; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D000099185:Interferon Regulatory Factor-8
D016207:Cytokines; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D020381:Interleukin-17; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D000099185:Interferon Regulatory Factor-8