title: Cytokine-like factor 1 gene expression is enriched in idiopathic pulmonary fibrosis and drives the accumulation of CD4+ T cells in murine lungs: evidence for an antifibrotic role in bleomycin injury.
abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive and typically fatal lung disease. To gain insight into the pathogenesis of IPF, we reanalyzed our previously published gene expression data profiling IPF lungs. Cytokine receptor-like factor 1 (CRLF1) was among the most highly up-regulated genes in IPF lungs, compared with normal controls. The protein product (CLF-1) and its partner, cardiotrophin-like cytokine (CLC), function as members of the interleukin 6 (IL-6) family of cytokines. Because of earlier work implicating IL-6 family members in IPF pathogenesis, we tested whether CLF-1 expression contributes to inflammation in experimental pulmonary fibrosis. In IPF, we detected CLF-1 expression in both type II alveolar epithelial cells and macrophages. We found that the receptor for CLF-1/CLC signaling, ciliary neurotrophic factor receptor (CNTFR), was expressed only in type II alveolar epithelial cells. Administration of CLF-1/CLC to both uninjured and bleomycin-injured mice led to the pulmonary accumulation of CD4(+) T cells. We also found that CLF-1/CLC administration increased inflammation but decreased pulmonary fibrosis. CLF-1/CLC leads to significantly enriched expression of T-cell-derived chemokines and cytokines, including the antifibrotic cytokine interferon-γ. We propose that, in IPF, CLF-1 is a selective stimulus of type II alveolar epithelial cells and may potentially drive an antifibrotic response by augmenting both T-helper-1-driven and T-regulatory-cell-driven inflammatory responses in the lung.
authors.affiliation: Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease and the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. kassd2@upmc.edu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Kass
authors.forename: Guoying
authors.initials: G
authors.lastname: Yu
authors.forename: Katrina S
authors.initials: KS
authors.lastname: Loh
authors.forename: Asaf
authors.initials: A
authors.lastname: Savir
authors.forename: Alain
authors.initials: A
authors.lastname: Borczuk
authors.forename: Rehan
authors.initials: R
authors.lastname: Kahloon
authors.forename: Brenda
authors.initials: B
authors.lastname: Juan-Guardela
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Deiuliis
authors.forename: John
authors.initials: J
authors.lastname: Tedrow
authors.forename: Jiin
authors.initials: J
authors.lastname: Choi
authors.forename: Thomas
authors.initials: T
authors.lastname: Richards
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.forename: Steven M
authors.initials: SM
authors.lastname: Greenberg
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D001761:Bleomycin; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D053739:Ciliary Neurotrophic Factor Receptor alpha Subunit / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004347:Drug Interactions; D004847:Epithelial Cells / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D051379:Mice; D011650:Pulmonary Alveoli / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018121:Receptors, Cytokine / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use / Q000633:toxicity; D015854:Up-Regulation / Q000502:physiology
chemical_list: C548324:CNTFR protein, human; D053739:Ciliary Neurotrophic Factor Receptor alpha Subunit; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D011994:Recombinant Proteins; C113554:cytokine-like factor-1; D001761:Bleomycin; D003094:Collagen