IL-4 regulates IL-12 p40 expression post-transcriptionally as well as via a promoter-based mechanism.
IL-12 and IL-4, respectively, dominate Th1 versus Th2 polarization. Additionally IL-4 can inhibit IL-12 p40 production in DC. Here we show that macrophages respond to bacterial CpG-DNA with IL-12 p40 production in an IL-4-sensitive manner. Analysis of the molecular mechanism of this inhibition shows that IL-4 acts by reducing the stability of IL-12 p40 mRNA as well as by affecting promoter activity. IL-4 did not affect early CpG-DNA-induced signal transduction. However, IL-4 reduced the activity of the IL-12 p40 promoter and when de novo transcription of IL-12 p40 mRNA was blocked, IL-4 led to acceleration of IL-12 p40 mRNA degradation. These data show that IL-4 regulates IL-12 p40 expression by influencing promoter activity and by interfering with mRNA stability.
Seegmüller
Irene
I
Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Germany.
Häcker
Hans
H
Wagner
Hermann
H
D000818:Animals; D002460:Cell Line / Q000187:drug effects; D018899:CpG Islands; D003609:Dactinomycin / Q000494:pharmacology; D017930:Genes, Reporter; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D053762:Interleukin-12 Subunit p40; D015847:Interleukin-4 / Q000494:pharmacology*; D008156:Luciferases / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D021122:Protein Subunits / Q000096:biosynthesis* / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection
D053762:Interleukin-12 Subunit p40; D019384:Nucleic Acid Synthesis Inhibitors; D021122:Protein Subunits; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D018664:Interleukin-12; D003609:Dactinomycin; D015847:Interleukin-4; D008156:Luciferases