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Here, we report that RNA sequencing of lung biopsies from patients with RA\u2010ILD and IPF revealed shared and distinct disease\u2010causing pathways. Analysis of transcriptomic data identified a JAK2 related JAK\/STAT signaling pathway gene signature that distinguishes RA\u2010UIP 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\u2010JAK2 in RA\u2010UIP (5\/5) and a minority of IPF (6\/20) cases. Further immunohistostaining identified STAT5A&amp;B as the downstream transcriptional activator for JAK2\u2010mediated canonical signal transduction and phosphorylation of Tyr41 on histone H3 (H3Y41ph) as the downstream epigenetic regulation site for JAK2\u2010mediated noncanonical signal transduction. Gene Set Enrichment Analysis (GSEA) of the RNA\u2010Seq data further supported this shared pathogenic mechanism for the two diseases with the enrichment of STAT5A&amp;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\u2010induced murine pulmonary fibrosis using a JAK2\u2010selective 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\u2010\u03b2\u2010mediated myofibroblast trans\u2010differentiation, proliferation, and extracellular matrix protein production. These observations support a crucial role for JAK2 as an intermediary molecule in fibrotic lung disease development.<\/jats:p>","DOI":"10.1096\/fj.202101436r","type":"journal-article","created":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T11:12:30Z","timestamp":1651835550000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Canonical and noncanonical regulatory roles for JAK2 in the pathogenesis of rheumatoid arthritis\u2010associated interstitial lung disease and idiopathic pulmonary fibrosis"],"prefix":"10.1096","volume":"36","author":[{"given":"Shaohua","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine Department of Medicine Mayo Clinic College of Medicine and Science  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengfei","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology Department of Medicine Mayo Clinic College of Medicine and Science  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiujuan","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Endocrinology Department of Medicine First Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Medicine Department of Medicine Chongqing General Hospital  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faping","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine West China Hospital Sichuan University  Chengdu 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Health Science Research Mayo Clinic College of Medicine and Science  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Sun","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine Department of Medicine Mayo Clinic College of Medicine and Science  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric L.","family":"Matteson","sequence":"additional","affiliation":[{"name":"Division of Rheumatology Department of Health Science Research Mayo Clinic College of Medicine and Science  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Tschumperlin","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering Mayo Clinic College of Medicine and Science  Rochester Minnesota 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