Canonical and noncanonical regulatory roles for JAK2 in the pathogenesis of rheumatoid arthritis-associated interstitial lung disease and idiopathic pulmonary fibrosis

作者全名："Wang, Shaohua; Liu, Mengfei; Li, Xiujuan; Zhang, Jie; Wang, Faping; Zhang, Chujie; Roden, Anja; Ryu, Jay H.; Warrington, Kenneth J.; Sun, Jie; Matteson, Eric L.; Tschumperlin, Daniel J.; Vassallo, Robert"

作者地址："[Wang, Shaohua; Zhang, Chujie; Ryu, Jay H.; Sun, Jie; Vassallo, Robert] Mayo Clin, Dept Med, Div Pulm & Crit Care Med, Coll Med & Sci, Rochester, MN 55902 USA; [Liu, Mengfei] Mayo Clin, Dept Med, Div Gastroenterol & Hepatol, Coll Med & Sci, Rochester, MN USA; [Li, Xiujuan] Chongqing Med Univ, Dept Med, Div Endocrinol, Affiliated Hosp 1, Chongqing, Peoples R China; [Zhang, Jie] Chongqing Gen Hosp, Dept Med, Div Pulm Med, Chongqing, Peoples R China; [Wang, Faping] Sichuan Univ, West China Hosp, Dept Resp & Crit Care Med, Chengdu, Peoples R China; [Roden, Anja] Mayo Clin, Dept Lab Med & Pathol, Coll Med & Sci, Rochester, MN USA; [Warrington, Kenneth J.; Matteson, Eric L.] Mayo Clin, Dept Hlth Sci Res, Div Rheumatol, Coll Med & Sci, Rochester, MN USA; [Tschumperlin, Daniel J.] Mayo Clin, Dept Physiol & Biomed Engn, Coll Med & Sci, Rochester, MN USA"

通信作者："Vassallo, R (通讯作者)，Mayo Clin, Dept Med, Div Pulm & Crit Care Med, Coll Med & Sci, Rochester, MN 55902 USA."

来源：FASEB JOURNAL

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000791483600001

JCR分区：Q1

影响因子：4.8

年份：2022

卷号：36

期号：6

开始页：　

结束页：　

文献类型：Article

关键词：idiopathic pulmonary fibrosis; interstitial lung disease; Janus kinase 2; rheumatoid arthritis; STAT3 transcription factor; STAT5 transcription factor

摘要："Idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated interstitial lung disease (RA-ILD) are two fibrotic interstitial lung diseases that share the usual interstitial pneumonia (UIP) injury pattern. Here, we report that RNA sequencing of lung biopsies from patients with RA-ILD and IPF revealed shared and distinct disease-causing pathways. Analysis of transcriptomic data identified a JAK2 related JAK/STAT signaling pathway gene signature that distinguishes RA-UIP from idiopathic UIP. This was further confirmed by immunohistostaining, which identified JAK2 phosphorylation with two distinct forms of activation: a cytoplasmic form of JAK2 activation in most IPF cases (13/20) and a nuclear form of p-JAK2 in RA-UIP (5/5) and a minority of IPF (6/20) cases. Further immunohistostaining identified STAT5A&B as the downstream transcriptional activator for JAK2-mediated canonical signal transduction and phosphorylation of Tyr41 on histone H3 (H3Y41ph) as the downstream epigenetic regulation site for JAK2-mediated noncanonical signal transduction. Gene Set Enrichment Analysis (GSEA) of the RNA-Seq data further supported this shared pathogenic mechanism for the two diseases with the enrichment of STAT5A&B target gene sets as well as the JAK2 regulated H3Y41ph target gene set. This regulatory role of JAK2 in the pathogenesis of pulmonary fibrosis was further demonstrated by the attenuation of bleomycin-induced murine pulmonary fibrosis using a JAK2-selective pharmacological inhibitor CEP33779. In vitro studies with normal and IPF derived lung fibroblasts revealed a central role for JAK2 as an essential intermediary molecule in TGF-beta-mediated myofibroblast trans-differentiation, proliferation, and extracellular matrix protein production. These observations support a crucial role for JAK2 as an intermediary molecule in fibrotic lung disease development."

基金机构：Rheumatology Research Foundation (RRF); Mayo Clinic (The Mayo Clinic); Pfizer

基金资助正文：Rheumatology Research Foundation (RRF); Mayo Clinic (The Mayo Clinic); Pfizer