Inhibition of collagen gene expression by interferon-γ: Novel role of the CCAAT/enhancer binding protein β (C/EBPβ)

Asish K Ghosh, Swati Bhattacharyya, Yasuji Mori, John Varga*

*Corresponding author for this work

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

By inhibiting collagen synthesis, interferon-γ (IFN-γ) plays a key role in maintaining connective tissue homeostasis, but the mechanisms are not well-understood. In addition to intracellular signaling through the canonical JAK-STAT transduction pathway, IFN-γ was recently shown to regulate gene expression via the CCAAT/enhancer-binding protein β (C/EBPβ) as well. Because C/EBPβ is a crucial mediator of immune and inflammatory responses, and has been implicated in regulation of collagen synthesis by tumor necrosis factor-α, we examined its role in the inhibitory effects of IFN-γ. The results demonstrated that IFN-γ caused increased C/EBPβ expression in dermal fibroblasts and enhanced its binding to cognate DNA sequences in the α2(I) procollagen gene (COL1A2) promoter in vitro and in vivo. Disruption of C/EBP binding by deletion or site-directed mutagenesis abrogated the inhibition of collagen promoter activity in transient transfection assays, as did cotransfection with dominant negative C/EBPβ, indicating a functional role of cellular C/EBPβ in mediating the IFN-γ response. Rapid phosphorylation of the ERK1/2 MAP kinases induced by IFN-γ was accompanied by phosphorylation and nuclear translocation of cellular C/EBPβ, and pretreatment of fibroblasts with ERK1/2 kinase inhibitor blocked C/EBPβ phosphorylation, as well as inhibition of COL1A2 promoter activity, elicited by IFN-γ. These results provide compelling evidence for a novel C/EBPβ-dependent IFN-γ signaling pathway responsible for inhibition of collagen gene transcription. Taken together with recent reports, the findings indicate that intracellular pathways mediating negative regulation of collagen synthesis in response to distinct inflammatory signals that converge on C/EBPβ.

Original languageEnglish (US)
Pages (from-to)251-260
Number of pages10
JournalJournal of Cellular Physiology
Volume207
Issue number1
DOIs
StatePublished - Apr 1 2006

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ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

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