title: Blockade of IL-6 Trans signaling attenuates pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with progressive fibrosis and death within 2-3 y of diagnosis. IPF incidence and prevalence rates are increasing annually with few effective treatments available. Inhibition of IL-6 results in the attenuation of pulmonary fibrosis in mice. It is unclear whether this is due to blockade of classical signaling, mediated by membrane-bound IL-6Rα, or trans signaling, mediated by soluble IL-6Rα (sIL-6Rα). Our study assessed the role of sIL-6Rα in IPF. We demonstrated elevations of sIL-6Rα in IPF patients and in mice during the onset and progression of fibrosis. We demonstrated that protease-mediated cleavage from lung macrophages was important in production of sIL-6Rα. In vivo neutralization of sIL-6Rα attenuated pulmonary fibrosis in mice as seen by reductions in myofibroblasts, fibronectin, and collagen in the lung. In vitro activation of IL-6 trans signaling enhanced fibroblast proliferation and extracellular matrix protein production, effects relevant in the progression of pulmonary fibrosis. Taken together, these findings demonstrate that the production of sIL-6Rα from macrophages in the diseased lung contributes to IL-6 trans signaling that in turn influences events crucial in pulmonary fibrosis.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030; University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030;
authors.forename: Thanh-Thuy T
authors.initials: TT
authors.lastname: Le
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030;
authors.forename: Harry
authors.initials: H
authors.lastname: Karmouty-Quintana
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Ernestina
authors.initials: E
authors.lastname: Melicoff
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030;
authors.forename: Thanh-Truc T
authors.initials: TT
authors.lastname: Le
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030;
authors.forename: Tingting
authors.initials: T
authors.lastname: Weng
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030;
authors.forename: Ning-Yuan
authors.initials: NY
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030; University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030; Biology of Inflammation Center, Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Mesias
authors.initials: M
authors.lastname: Pedroza
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030;
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Jonathan
authors.initials: J
authors.lastname: Davies
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030;
authors.forename: Kemly
authors.initials: K
authors.lastname: Philip
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030;
authors.forename: Jose
authors.initials: J
authors.lastname: Molina
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030;
authors.forename: Fayong
authors.initials: F
authors.lastname: Luo
authors.affiliation: Biology of Inflammation Center, Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Anuh T
authors.initials: AT
authors.lastname: George
authors.affiliation: Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX 77030; and.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Garcia-Morales
authors.affiliation: Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX 77030; and.
authors.forename: Raquel R
authors.initials: RR
authors.lastname: Bunge
authors.affiliation: Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX 77030; and Methodist J.C. Walter Jr. Transplant Center, The Methodist Hospital, Houston, TX 77030.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Bruckner
authors.affiliation: Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, TX 77030; and Methodist J.C. Walter Jr. Transplant Center, The Methodist Hospital, Houston, TX 77030.
authors.forename: Matthias
authors.initials: M
authors.lastname: Loebe
authors.affiliation: Methodist J.C. Walter Jr. Transplant Center, The Methodist Hospital, Houston, TX 77030.
authors.forename: Harish
authors.initials: H
authors.lastname: Seethamraju
authors.affiliation: Biology of Inflammation Center, Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Agarwal
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030; University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030; michael.r.blackburn@uth.tmc.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
mesh_terms: D000818:Animals; D003094:Collagen / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005353:Fibronectins / Q000276:immunology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D058628:Myofibroblasts / Q000276:immunology / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D005353:Fibronectins; C508600:IL6 protein, human; C508603:IL6R protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D003094:Collagen