IL-6 regulates induction of C-reactive protein gene expression by activating STAT3 isoforms. (June 2022)

• Record Type: Journal Article
• Authors: Ngwa, Donald N.; Pathak, Asmita; Agrawal, Alok
• Is Part Of: Molecular immunology. Volume 146(2022)
• Page Start: 50
• Page End: 56
• Publication Date: 2022-06
• Subjects: CRP C-reactive protein -- EMSA electrophoretic mobility shift assay -- Luc luciferase -- Oligo oligonucleotide -- WT wild-type; Acute phase protein -- Acute phase response -- C-reactive protein -- STAT3 isoform; Immunochemistry -- Periodicals; Molecular biology -- Periodicals; Immunochemistry -- Periodicals; Allergy and Immunology -- Periodicals; Molecular Biology -- Periodicals; Immunochimie -- Périodiques; Biologie moléculaire -- Périodiques; Immunochemistry; Molecular biology; Periodicals; Electronic journals; 571.96
• DOI: 10.1016/j.molimm.2022.04.003
• Languages: English
• ISSNs: 0161-5890

Abstract

Abstract: C-reactive protein (CRP) is synthesized in hepatocytes. The serum concentration of CRP increases dramatically during the acute phase response. In human hepatoma Hep3B cells, maximal CRP expression occurs in cells treated with the combination of IL-6 and IL-1β. IL-6 induces transcription of the CRP gene and IL-1β synergistically enhances the effects of IL-6. We investigated the role of IL-6-activated transcription factor STAT3, also known as STAT3α, in inducing CRP expression since we identified four consensus STAT3-binding sites centered at positions − 72, − 108, − 134 and − 164 on the CRP promoter. It has been shown previously that STAT3 binds to the site at − 108 and induces CRP expression. We found that STAT3 also bound to the other three sites, and several STAT3-containing complexes were formed at each site, suggesting the presence of STAT3 isoforms and additional transcription factors in the complexes. Mutation of the STAT3 sites at − 108, − 134 or − 164 resulted in decreased CRP expression in response to IL-6 and IL-1β treatment, although the synergy between IL-6 and IL-1β was not affected by the mutations. The STAT3 site at − 72 could not be investigated employing mutagenesis. We also found that IL-6 activated two isoforms of STAT3 in Hep3B cells: STAT3α which contains both a DNA-binding domain and a transactivation domain and STAT3β which contains only the DNA-binding domain. Taken together, these findings raise the possibility that IL-6 not only induces CRP expression but also regulates the induction of CRP expression by activating STAT3 isoforms and by utilizing all four STAT3 sites. Highlights: There are four STAT3 sites on the CRP proximal promoter. IL-6 activates two STAT3 isoforms in Hep3B cells. Multiple STAT3-complexes of varying compositions form at the STAT3 sites. IL-6 not only activates but also regulates the activation of CRP expression.