HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Interleukin 1b inhibits interleukin 6–mediated rat g fibrinogen gene expression

Interleukin (IL)-1b 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-1b exerts a transient inhibitory effect over the IL-6 stimulatory signal. This study explored the effects of IL-1b/nuclear factor kB (NF-kB) and IL-6/ signal transducer and activator of transcription 3 (STAT3) combinatory signaling on the transcriptional regulation of the rat g fibrinogen gene. Northern blot and functional analyses employing luciferase reporter constructs driven by the rat g fibrinogen promoter demonstrated that IL-1b inhibited the IL-6-mediated transcription of this gene. Exposing primary rat hepatocytes to IL-1b had no effect on IL-6-mediated STAT3 activation; instead, IL-1b-activated NF-kB associated with 2 IL-6 responsive elements (STAT3 binding site) on the rat g fibrinogen promoter and blocked STAT3 binding to these regions. The competitive binding of NF-kB and STAT3 on the overlapping binding site provides a mechanism for the inhibition by IL-1b of the IL-6-mediated transactivation of rat g fibrinogen. (Blood. 2000;96: 3466-3472)