TY - JOUR
T1 - Blockade of IL-6 trans signaling attenuates pulmonary fibrosis
AU - Le Thanh-Thuy, T.
AU - Karmouty-Quintana, Harry
AU - Melicoff, Ernestina
AU - Le Thanh-Truc, T.
AU - Weng, Tingting
AU - Chen, Ning Yuan
AU - Pedroza, Mesias
AU - Zhou, Yang
AU - Davies, Jonathan
AU - Philip, Kemly
AU - Molina, Jose
AU - Luo, Fayong
AU - George, Anuh T.
AU - Garcia-Morales, Luis J.
AU - Bunge, Raquel R.
AU - Bruckner, Brian A.
AU - Loebe, Matthias
AU - Seethamraju, Harish
AU - Agarwal, Sandeep K.
AU - Blackburn, Michael R.
N1 - Publisher Copyright:
© 2014 by The American Association of Immunologists, Inc.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - 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-6Ra, or trans signaling, mediated by soluble IL-6Ra (sIL-6Ra). Our study assessed the role of sIL-6Ra in IPF. We demonstrated elevations of sIL-6Ra 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-6Ra. In vivo neutralization of sIL-6Ra 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- 6Ra from macrophages in the diseased lung contributes to IL-6 trans signaling that in turn influences events crucial in pulmonary fibrosis.
AB - 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-6Ra, or trans signaling, mediated by soluble IL-6Ra (sIL-6Ra). Our study assessed the role of sIL-6Ra in IPF. We demonstrated elevations of sIL-6Ra 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-6Ra. In vivo neutralization of sIL-6Ra 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- 6Ra from macrophages in the diseased lung contributes to IL-6 trans signaling that in turn influences events crucial in pulmonary fibrosis.
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U2 - 10.4049/jimmunol.1302470
DO - 10.4049/jimmunol.1302470
M3 - Article
C2 - 25172494
AN - SCOPUS:84907222985
SN - 0022-1767
VL - 193
SP - 3755
EP - 3768
JO - Journal of Immunology
JF - Journal of Immunology
IS - 7
ER -