Blockade of IL-6 Trans Signaling Attenuates Pulmonary Fibrosis

• Published in: The Journal of immunology (1950) Vol. 193; no. 7; pp. 3755 - 3768
• Main Authors: Le, Thanh-Thuy T, Karmouty-Quintana, Harry, Melicoff, Ernestina, Le, Thanh-Truc T, Weng, Tingting, Chen, Ning-Yuan, Pedroza, Mesias, Zhou, Yang, Davies, Jonathan, Philip, Kemly, Molina, Jose, Luo, Fayong, George, Anuh T, Garcia-Morales, Luis J, Bunge, Raquel R, Bruckner, Brian A, Loebe, Matthias, Seethamraju, Harish, Agarwal, Sandeep K, Blackburn, Michael R
• Format: Journal Article
• Language: English
• Published: United States AAI 01.10.2014
• Subjects: Animals; Collagen - immunology; Disease Models, Animal; Female; Fibronectins - immunology; Humans; Idiopathic Pulmonary Fibrosis - genetics; Idiopathic Pulmonary Fibrosis - immunology; Idiopathic Pulmonary Fibrosis - mortality; Idiopathic Pulmonary Fibrosis - pathology; Idiopathic Pulmonary Fibrosis - therapy; Interleukin-6 - genetics; Interleukin-6 - immunology; Lung - immunology; Lung - pathology; Macrophages, Alveolar - immunology; Macrophages, Alveolar - pathology; Male; Mice; Molecular and Structural Immunology; Myofibroblasts - immunology; Myofibroblasts - pathology; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - immunology; Pulmonary Fibrosis - pathology; Receptors, Interleukin-6 - immunology; Signal Transduction - immunology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1302470

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.