Interleukin-1β Induces Increased Transcriptional Activation of the Transforming Growth Factor-β-activating Integrin Subunit β8 through Altering Chromatin Architecture

Abstract

Background: IL-1␤ acts on fibroblasts inducing TGF-␤-dependent profibrogenic responses. Results: IL-1␤ increases expression of the TGF-␤-activating integrin ␤8 subunit through altering nucleosomal positioning at the ITGB8 promoter. Conclusion: IL-1␤ increases accessibility of transcription factors to the ITGB8 promoter in lung fibroblasts through chromatin remodeling.Significance: This provides evidence for chromatin architectural changes mediating IL-1␤ profibrotic programs.

Transforming Growth Factor-β and Interleukin-1β Signaling Pathways Converge on the Chemokine CCL20 Promoter

“…We have previously determined that IL-1␤ increases the expression of ␣v␤8 by fibroblasts, yet here we failed to find a significant correlation between IL-1␤ and ␣v␤8 levels (30). It is possible that our relatively large cohort was still underpowered to find a correlation.…”

“…Promoter Assays, Chromatin Immunoprecipitations, Transfections, and TFG-␤ Activation Assays-These assays were performed essentially, as described (4,6,22,30). For ChIP, 5 g/IP of anti-SMAD4 (Santa Cruz Biotechnology, Santa Cruz, CA) and 1 g/IP of anti-p50 (Cell Signaling) were used.…”

“…Increased immunohistochemical staining of ␣v␤8 in airway fibroblasts correlates with disease severity in COPD lungs (4,30). Intratracheal adenoviral (Ad) delivery of IL-1␤ to the airways of mice leads to increased ␣v␤8 expression (6), through a transcriptional pathway involving AP-1 and SP3 (30).…”

“…Increased immunohistochemical staining of ␣v␤8 in airway fibroblasts correlates with disease severity in COPD lungs (4,30). Intratracheal adenoviral (Ad) delivery of IL-1␤ to the airways of mice leads to increased ␣v␤8 expression (6), through a transcriptional pathway involving AP-1 and SP3 (30). The expression of ␣v␤8 by fibroblasts appears to be particularly important because fibroblast conditional deletion of itgb8 prevents Ad-IL-1␤-induced airway inflammation and fibrosis, implicating fibroblasts as a cell type involved in driving both the inflammatory and fibrotic response during airway remodeling (6).…”

ABCG2pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling

“…Secretoglobin3A2 (scgb3a2) inhibits TGF-␤-induced myofibroblast differentiation in part via regulation of SMAD2 (56). SMAD 2 mediates TGF-␤ signaling while integrin subunit beta8 (Itgb8) expression is increased with inflammation and results in TGF-␤ activation (with ␣ v subunit) by fibroblasts (41,61). This activation of TGF-␤ results in myofibroblast transition of fibroblasts as well as EC, increased collagen deposition (col1a1, col3a1), increased matrix stiffening, and adverse remodeling (41,46).…”