Overexpressed nuclear factor‐κB can participate in endogenous C‐reactive protein induction, and enhances the effects of C/EBPβ and signal transducer and activator of transcription‐3

Abstract

SUMMARYC-reactive protein (CRP), the prototypical human acute phase protein, is produced primarily by hepatocytes. Its expression is modestly induced by interleukin (IL)-6 in Hep3B cells while IL-1, which alone has no effect, synergistically enhances the effects of IL-6. In previous studies of the proximal CRP promoter, we found that signal transducer and activator of transcription-3 (STAT3) and C/EBPb -mediated IL-6-induced transcription and that Rel p50 acted synergistically with C/ EBPb, in the absence of p65, to enhance CRP transcription. Neither a requirement nor a binding site for the classic nuclear factor (NF)-kB heterodimer p50/p65 were found. The current studies were undertaken to determine whether similar novel transcription factor interactions might regulate the endogenous CRP gene. Transiently overexpressed p50 or p65 induced CRP mRNA accumulation in Hep3B cells. The heterodimer p50/p65 was markedly more effective than p50 or p65 homodimers. Co-overexpression of p50 or p65 with C/EBPb or STAT3 synergistically enhanced CRP expression. Maximal expression was observed with overexpression of all four transcription factors; comparable effects were observed with IL-1b treatment of cells overexpressing STAT3 C/EBPb. Data from the Human Genome Project revealed 13 potential kB sites in the ®rst 4000 bases of the CRP promoter, only one of which, centred at À2652, bound nuclear p50/p65 heterodimer activated by IL-1b. Our ®ndings indicate that classical NF-kB activation can participate in endogenous CRP induction, and that activated NF-kB may synergistically enhance the effects of C/EBPb and STAT3. They raise the possibility, not as yet established, that NF-kB activation may be responsible for the synergistic effect of IL-1b on IL-6-induced CRP expression.

Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFκB

“…U-STAT3 binds to both p65 and p50, and a specific type of B sequence motif supports both the binding of p65 homodimers and cooperativity with U-STAT3 (Yoshida et al 2004). Agrawal et al (2003) showed that P-NF B synergistically cooperates with P-STAT3 and C/EBP␤ to enhance transcription of the Creactive protein (CRP) gene. Hagihara et al (2005) found that STAT3 plays an essential role in cytokine-driven expression of the serum amyloid A (SAA) gene, which does not have a typical STAT3 response element in its promoter.…”

Statins and nitric oxide reduce C-reactive protein production while inflammatory conditions persist

“…In Hep3B cells, transcription factors C/EBP (Li and Goldman, 1996;Agrawal et al, 2001Agrawal et al, , 2003aCha-Molstad et al, 2000), STAT3 (Zhang et al, 1996) and NF-B (Agrawal et al, 2003b) participate in the induction of CRP expression. On the CRP promoter, transcription factor C/EBP binds to a site at -52, STAT3 binds to a site at -108 and NF-B binds to a site at -69 (Li and Goldman, 1996;Zhang et al, 1996;Voleti and Agrawal, 2004).…”

A Nuclear Receptor Corepressor–Dependent Pathway Mediates Suppression of Cytokine-Induced C-Reactive Protein Gene Expression by Liver X Receptor

“…18 The transcription factors STAT3 (Signal Transducer and Activator of Transcription 3), nuclear factor B and members of the C/EBP family (CCAAT box/ Enhancer-Binding Protein) participate in cytokine-induced transcriptional activation of the CRP gene. 19,20 In addition, hepatocyte nuclear factor-1 (HNF-1), HNF-3, and Oct-1 also play important roles in the regulation of CRP expression. [21][22][23] The liver X receptors ␣ (LXR␣) and LXR␤ (also known as NR1H3 and NR1H2, respectively) are members of the nuclear hormone receptor superfamily and have been suggested as potential targets for therapeutic intervention in human cardiovascular and metabolic disease.…”