Involvement of STAT-1 and ets family members in interferon-gamma induction of CD40 transcription in microglia/macrophages.
Cluster of differentiation (CD)-40 is a cell surface receptor belonging to the tumor necrosis factor receptor family that plays a critical role in the regulation of immune responses. We have previously shown that the cytokine interferon (IFN)-gamma induces CD40 expression in microglia. Herein, we have elucidated the molecular mechanisms underlying IFN-gamma induction of CD40 gene expression in microglia/macrophages. IFN-gamma up-regulates CD40 expression at the transcriptional level, and this regulation involves the STAT-1alpha transcription factor. Microglia from STAT-1alpha-deficient mice were refractive to IFN-gamma induction of CD40 expression, illustrating the importance of STAT-1alpha in this response. Functional analysis of the CD40 promoter indicates that two gamma activated sequence elements as well as two Ets elements are involved in IFN-gamma induction of CD40 promoter activity. STAT-1alpha binds to the gamma activated sequence elements, whereas PU.1 and/or Spi-B bind to the Ets elements. The expression of PU.1 and Spi-B, in conjuction with STAT-1alpha activation, correlates with IFN-gamma inducibility of CD40 expression. Collectively, our data demonstrate the involvement of STAT-1alpha, PU.1, and Spi-B in IFN-gamma induction of CD40 gene expression in cells of the macrophage lineage.
Nguyen
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VT
Department of Cell Biology, The Univeristy of Alabama at Birmingham, Birmingham, Alabama 35294-0005, USA.
Benveniste
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EN
D000818:Animals; D001483:Base Sequence; D019013:CD40 Antigens / Q000096:biosynthesis / Q000235:genetics*; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D017628:Microglia / Q000166:cytology* / Q000378:metabolism; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D012045:Regulatory Sequences, Nucleic Acid; D050794:STAT1 Transcription Factor; D017384:Sequence Deletion; D012689:Sequence Homology, Nucleic Acid; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation; D000099232:Proto-Oncogene Protein Spi-1
D019013:CD40 Antigens; D004268:DNA-Binding Proteins; D007371:Interferon-gamma; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C494080:Stat1 protein, mouse; C076877:SPIB protein, human