Yin Yang‐1 suppresses CD40 ligand‐CD40 signaling‐mediated anti‐inflammatory cytokine interleukin‐10 expression in pulmonary adventitial fibroblasts by promoting histone H3 tri‐methylation at lysine 27 modification on interleukin‐10 promoter

• Published in: Cell biology international Vol. 44; no. 7; pp. 1544 - 1555
• Main Authors: Pan, Yan‐Yun, Yang, Jin‐Xiu, Xu, Yi‐Fei, Mao, Wei
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.07.2020
• Subjects: Animals; Anti-Inflammatory Agents - metabolism; Anti-Inflammatory Agents - pharmacology; CD40; CD40 antigen; CD40 Antigens - metabolism; CD40 ligand; CD40 Ligand - genetics; CD40 Ligand - metabolism; CD40L protein; Cytokines; DNA methylation; Enhancer of Zeste Homolog 2 Protein - genetics; epigenetic modification; Fibroblasts; Fibroblasts - metabolism; Gene expression; Histone H3; Histone methyltransferase; Histones - metabolism; Inflammation; Interleukin 10; Interleukin-10 - metabolism; Ligands; Lysine; Lysine - metabolism; mRNA turnover; N6-methyladenosine; Phenotypes; Promoter Regions, Genetic - physiology; Protein expression; Proteins; pulmonary arterial hypertension; pulmonary artery adventitial fibroblasts; Rats, Sprague-Dawley; Up-Regulation; Vasoconstriction; Yin Yang 1; YY1 Transcription Factor - metabolism; Yin Yang 1; epigenetic modification; CD40; pulmonary arterial hypertension; CD40 ligand; pulmonary artery adventitial fibroblasts
• ISSN: 1065-6995; 1095-8355
• DOI: 10.1002/cbin.11351

During the pathogenesis of early pulmonary arterial hypertension (PAH), pulmonary arterial adventitial fibroblast act as an initiator and mediator of inflammatory processes that predispose vessel walls to excessive vasoconstriction and pathogenic vascular remodeling. Emerging studies report that Yin Yang‐1 (YY‐1) plays important roles in inflammatory response and vascular injury. Our recent study finds that activation of CD40 ligand (CD40L)–CD40 signaling promotes pro‐inflammatory phenotype of pulmonary adventitial fibroblasts. However, whether YY‐1 is involved in CD40L–CD40 signaling‐triggered inflammatory response in pulmonary adventitial fibroblasts and its underlying mechanism is still unclear. Here, we show that soluble CD40L (sCD40L) stimulation promotes YY‐1 protein expression and suppresses anti‐inflammatory cytokine, interleukin 10 (IL‐10) expression in pulmonary adventitial fibroblasts, while YY‐1 knockdown prevents sCD40L‐mediated reduction of IL‐10 expression via enhancing IL‐10 gene transactivation. Further, we find that sCD40L stimulation significantly increases histone H3 tri‐methylation at lysine 27 (H3K27me3) modification on IL‐10 promoter in pulmonary adventitial fibroblasts, and YY‐1 knockdown prevents the effect of sCD40L on IL‐10 promoter by reducing the interaction with enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, binding to IL‐10 promoter. Moreover, we find that sCD40L stimulation promotes YY‐1 protein, but not messenger RNA (mRNA) expression, via decreasing N6‐methyladenosine methylation on YY‐1 mRNA to suppress YTHDF2‐medicated mRNA decay. Overall, this in‐depth study shows that the activation of CD40L‐CD40 signaling upregulates YY‐1 protein expression in pulmonary adventitial fibroblasts, which results in increasing YY‐1 and EZH2 binding to the IL‐10 promoter region to enhance H3K27me3 modification, eventually leading to suppression of IL‐10 transactivation. This study first uncovers the roles of YY‐1 on CD40L‐CD40 signaling‐triggered inflammatory response in pulmonary adventitial fibroblasts.