Interleukin 1beta inhibits interleukin 6-mediated rat gamma fibrinogen gene expression.
Interleukin (IL)-1beta and IL-6 are the 2 major inducers of a group of hepatic genes during acute inflammation; however, each cytokine uses different intracellular signaling molecules. In most instances, the 2 cytokines interact positively to enhance hepatic gene expression, but in one class of acute-phase reactants, which includes fibrinogen, IL-1beta exerts a transient inhibitory effect over the IL-6 stimulatory signal. This study explored the effects of IL-1beta/nuclear factor kappaB (NF-kappaB) and IL-6/signal transducer and activator of transcription 3 (STAT3) combinatory signaling on the transcriptional regulation of the rat gamma fibrinogen gene. Northern blot and functional analyses employing luciferase reporter constructs driven by the rat gamma fibrinogen promoter demonstrated that IL-1beta inhibited the IL-6-mediated transcription of this gene. Exposing primary rat hepatocytes to IL-1beta had no effect on IL-6-mediated STAT3 activation; instead, IL-1beta-activated NF-kappaB associated with 2 IL-6 responsive elements (STAT3 binding site) on the rat gamma fibrinogen promoter and blocked STAT3 binding to these regions. The competitive binding of NF-kappaB and STAT3 on the overlapping binding site provides a mechanism for the inhibition by IL-1beta of the IL-6-mediated transactivation of rat gamma fibrinogen.
Zhang
Z
Z
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
Fuller
G M
GM
D021581:Active Transport, Cell Nucleus; D000209:Acute-Phase Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D015342:DNA Probes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005340:Fibrinogen / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits; D019947:Receptors, Interleukin-6 / Q000235:genetics; D020218:Response Elements / Q000187:drug effects; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA
D000209:Acute-Phase Proteins; D015342:DNA Probes; D004268:DNA-Binding Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D021122:Protein Subunits; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D051996:Transcription Factor RelA; D005340:Fibrinogen; D008156:Luciferases