NF-κB and Activator Protein 1 Response Elements and the Role of Histone Modifications in IL-1β-Induced TGF-β1 Gene Transcription

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.

Interleukin‐1β impairment of transforming growth factor β1 signaling by DOWN‐REGULATION of transforming growth factor β receptor type II and up‐regulation of Smad7 in human articular chondrocytes

“…They cooperate to regulate the expression of the TGF␤1 gene upon IL-1␤ stimulation (31). Moreover, it has been reported that Jun or Fos can interact with the p65 subunit of NF-B (44).…”

Interaction Among Heme Oxygenase, Nuclear Factor-κB, and Transcription Activating Factors in Cardiac Hypertrophy in Hypertension

“…6 Accordingly, the high levels of 8-isoprostane alongside increased NF-B, AP-1, AP-2, and JNK observed in DOCAhypertensive rats may act in concert with elevated TGF-␤ 1 , fibronectin, and collagen-1 to accentuate the oxidative and fibrotic destruction of cardiac tissues. [3][4][5]7 Interestingly, upregulating the HO system abated these destructive factors and attenuated cardiac lesions, whereas the HO inhibitor, CrMP, exacerbated cardiac hypertrophy. Although many HO inhibitors are nonspecific, CrMP given at a dose of 4 mol/kg is selective against HO.…”

“…7,8 Moreover, in DOCA-salt hypertension, locally produced aldosterone in cardiac tissue 3 stimulates TGF-␤ 1 , fibronectin, and collagen-1 causing fibrosis and hypertrophy. 4 Because the TGF-␤ 1 gene promoter contains binding sites for NF-〉 and AP-1, 5 crosstalk among TGF-␤ 1 , NF-〉, and AP-1 is envisaged. Thus, the activation of TGF-␤ 1 , fibronectin, NF-〉, AP-1, and JNK may constitute a potent destructive force in hypertension.…”

“…1,2 In mineralocorticoid-induced hypertension, the activation of JNK, TGF-␤ (TGF-␤ 1 ) and NF-B constitutes a potent prohypertrophic/remodeling axis. [2][3][4][5] The pathophysiological role of aldosterone in cardiac damage is evident in deoxycorticosterone acetate-salt (DOCA-salt) hypertension, 6 where elevated superoxide quenches NO to form peroxynitrite and 8-isoprostane, with subsequent stimulation of endothelin-1 to potentiate oxidative injury. 7,8 Moreover, in DOCA-salt hypertension, locally produced aldosterone in cardiac tissue 3 stimulates TGF-␤ 1 , fibronectin, and collagen-1 causing fibrosis and hypertrophy.…”

Regulation of matrix metalloproteinase gene expression by a retinoid X receptor–specific ligand

“…These complexes mobilize nucleosomes, allowing the transcriptional machinery better access to the DNA to be transcribed and leading to increased transcription (38). Up-regulation of target genes by IL-1␤ has been linked to increased histone acetylation at AP-1-specific promoter sites (39). Thus, we hypothesized that if the proximal AP-1 sites in the MMP-1 and MMP-13 promoters were targets of LG268-mediated inhibition,…”