Synergistic activation of interleukin-12 p35 gene transcription by interferon regulatory factor-1 and interferon consensus sequence-binding protein.
Interferon regulatory factor-1 (IRF-1) and interferon consensus sequence-binding protein (ICSBP or IRF-8) are two members of the IRF family of transcription factors that play critical roles in interferon signaling in a wide range of host responses to infection and malignancy. Interleukin-12 (IL-12) is a key factor in the induction of innate resistance and generation of T helper type 1 cells and cytotoxic T lymphocytes. In this work, we find that ICSBP-deficient macrophages are highly defective in the production of IL-12. The defect is also observed at the level of IL-12 p40 and p35 mRNA expression. Transcriptional analyses revealed that ICSBP is a potent activator of the IL-12 p35 gene. It acts through a site localized to -226 to -219, named ICSBP-response element (ICSBP-RE), in the human IL-12 p35 promoter through physical association with IRF-1 both in vitro and in vivo. Co-expression of ICSBP and IRF-1 synergistically stimulates the IL-12 p35 promoter activity. Mutations at the ICSBP-RE results in the loss of protein binding as well as transcriptional activation by ICSBP alone or together with IRF-1. This study provides novel mechanistic information on how signals initiated during innate and adaptive immune responses synergize to yield greater IL-12 production and sustained cellular immunity.
Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Jianguo
J
Liu
Xiuqin
X
Guan
Tomohiko
T
Tamura
Keiko
K
Ozato
Xiaojing
X
Ma
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D047468:Immunoprecipitation; D007249:Inflammation; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D007372:Interferons; D018664:Interleukin-12 / Q000378:metabolism / Q000502:physiology*; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D000099185:Interferon Regulatory Factor-8
D004247:DNA; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D007372:Interferons; D018664:Interleukin-12; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; D010750:Phosphoproteins; D021122:Protein Subunits; D012333:RNA, Messenger; D012097:Repressor Proteins; D012260:Ribonucleases; D000099185:Interferon Regulatory Factor-8; C508858:IL12A protein, human; C494257:IRF1 protein, human; C494258:Irf1 protein, mouse