NF-κB and activator protein 1 response elements and the role of histone modifications in IL-1β-induced TGF-β1 gene transcription

Kang Yun Lee, Kazuhiro Ito, Ryuji Hayashi, Elen P I Jazrawi, Peter J. Barnes, Ian M. Adcock

Research output: Contribution to journalArticle

134 Citations (Scopus)

Abstract

Abnormal expression of TGF-β1 is believed to play an important role in the pathogenesis of a number of chronic inflammatory and immune lung diseases, including asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. Gene activation in eukaryotes requires coordinated use of specific cell signals, chromatin modifications, and chromatin remodeling. We studied the roles of the ubiquitous inflammatory transcription factors, NF-κB and AP-1, in activation of the TGF-β1 gene and histone acetylation at the TGF-β1 promoter. IL-1β-induced TGF-β1 protein secretion and mRNA expression were prevented by actinomycin D and were attenuated by the inhibitor of κB kinase 2 inhibitor AS602868 and the JNK inhibitor SP600125, suggesting a degree of transcriptional regulation mediated by the NF-κB and AP-1 pathways. We demonstrated that IL-1β activated the p65 subunit of NF-κB and the c-Jun subunit of AP-1. Using chromatin immunoprecipitation assays, we observed a sequential recruitment of p65 and c-Jun, accompanying ordered elevation of the levels of histone H4 and H3 acetylation and recruitment of RNA polymerase II at distinct regions in the native TGF-β1 promoter. The specific NF-κB and AP-1 binding sites in the TGF-β1 promoter were confirmed by an ELISA-based binding assay, and evidence for histone hyperacetylation in TGF-β1 induction was supported by the observation that the histone deacetylase inhibitor trichostatin A enhanced basal and IL-1β-induced TGF-β1 mRNA expression. Our results suggest that IL-1β-stimulated transcription of TGF-β1 is temporally regulated by NF-κB and AP-1 and involves histone hyperacetylation at distinct promoter sites.

Original languageEnglish
Pages (from-to)603-615
Number of pages13
JournalJournal of Immunology
Volume176
Issue number1
Publication statusPublished - Jan 1 2006
Externally publishedYes

ASJC Scopus subject areas

  • Immunology

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