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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.

Blockade of IL-6 Trans Signaling Attenuates Pulmonary Fibrosis

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  • Media type: E-Article
  • Title: Blockade of IL-6 Trans Signaling Attenuates Pulmonary Fibrosis
  • Contributor: 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.
  • Published: The American Association of Immunologists, 2014
  • Published in: The Journal of Immunology, 193 (2014) 7, Seite 3755-3768
  • Language: English
  • DOI: 10.4049/jimmunol.1302470
  • ISSN: 0022-1767; 1550-6606
  • Origination:
  • Footnote:
  • Description: 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.
  • Access State: Open Access