Therapeutic targeting of the IL-6 trans-signaling/mechanistic target of rapamycin complex 1 axis in pulmonary emphysema

Saleela M. Ruwanpura, Louise McLeod, Lovisa F. Dousha, Huei Jiunn Seow, Sultan Alhayyani, Michelle D. Tate, Virginie Deswaerte, Gavin D. Brooks, Steven Bozinovski, Martin MacDonald, Christoph Garbers, Paul T. King, Philip G. Bardin, Ross Vlahos, Stefan Rose-John, Gary P. Anderson, Brendan J. Jenkins

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)

Abstract

Rationale: The potent immunomodulatory cytokine IL-6 is consistently up-regulated in human lungs with emphysema and in mouse emphysema models; however, the mechanisms by which IL-6 promotes emphysema remain obscure. IL-6 signals using two distinct modes: classical signaling via its membrane-bound IL-6 receptor (IL-6R), and trans-signaling via a naturally occurring soluble IL-6R. Objectives: To identify whether IL-6 trans-signaling and/or classical signaling contribute to the pathogenesis of emphysema. Methods: We used the gp130F/F genetic mouse model for spontaneous emphysema and cigarette smoke-induced emphysema models. Emphysema in mice was quantified by various methods including in vivo lung function and stereology, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to assess alveolar cell apoptosis. In mouse and human lung tissues, the expression level and location of IL-6 signaling-related genes and proteinsweremeasured, and the levels of IL-6 and related proteins in sera from emphysematous mice and patients were also assessed. Measurements and Main Results: Lung tissues from patients with emphysema, and from spontaneous and cigarette smoke-induced emphysema mouse models, were characterized by excessive production of soluble IL-6R. Genetic blockade of IL-6 trans-signaling in emphysema mouse models and therapy with the IL-6 trans-signaling antagonist sgp130Fc ameliorated emphysema by suppressing augmented alveolar type II cell apoptosis. Furthermore, IL-6 trans-signaling-driven emphysematous changes in the lung correlated with mechanistic target of rapamycin complex 1 hyperactivation, and treatment of emphysema mouse models with the mechanistic target of rapamycin complex 1 inhibitor rapamycin attenuated emphysematous changes. Conclusions: Collectively, our data reveal that specific targeting of IL-6 trans-signaling may represent a novel treatment strategy for emphysema.

Original languageEnglish
Pages (from-to)1494-1505
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume194
Issue number12
DOIs
Publication statusPublished - 15 Dec 2016

Keywords

  • Interleukin-6
  • Mechanistic target of rapamycin complex 1
  • Mouse models
  • Pulmonary emphysema
  • Trans-signaling

Cite this

Ruwanpura, Saleela M. ; McLeod, Louise ; Dousha, Lovisa F. ; Seow, Huei Jiunn ; Alhayyani, Sultan ; Tate, Michelle D. ; Deswaerte, Virginie ; Brooks, Gavin D. ; Bozinovski, Steven ; MacDonald, Martin ; Garbers, Christoph ; King, Paul T. ; Bardin, Philip G. ; Vlahos, Ross ; Rose-John, Stefan ; Anderson, Gary P. ; Jenkins, Brendan J. / Therapeutic targeting of the IL-6 trans-signaling/mechanistic target of rapamycin complex 1 axis in pulmonary emphysema. In: American Journal of Respiratory and Critical Care Medicine. 2016 ; Vol. 194, No. 12. pp. 1494-1505.
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title = "Therapeutic targeting of the IL-6 trans-signaling/mechanistic target of rapamycin complex 1 axis in pulmonary emphysema",
abstract = "Rationale: The potent immunomodulatory cytokine IL-6 is consistently up-regulated in human lungs with emphysema and in mouse emphysema models; however, the mechanisms by which IL-6 promotes emphysema remain obscure. IL-6 signals using two distinct modes: classical signaling via its membrane-bound IL-6 receptor (IL-6R), and trans-signaling via a naturally occurring soluble IL-6R. Objectives: To identify whether IL-6 trans-signaling and/or classical signaling contribute to the pathogenesis of emphysema. Methods: We used the gp130F/F genetic mouse model for spontaneous emphysema and cigarette smoke-induced emphysema models. Emphysema in mice was quantified by various methods including in vivo lung function and stereology, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to assess alveolar cell apoptosis. In mouse and human lung tissues, the expression level and location of IL-6 signaling-related genes and proteinsweremeasured, and the levels of IL-6 and related proteins in sera from emphysematous mice and patients were also assessed. Measurements and Main Results: Lung tissues from patients with emphysema, and from spontaneous and cigarette smoke-induced emphysema mouse models, were characterized by excessive production of soluble IL-6R. Genetic blockade of IL-6 trans-signaling in emphysema mouse models and therapy with the IL-6 trans-signaling antagonist sgp130Fc ameliorated emphysema by suppressing augmented alveolar type II cell apoptosis. Furthermore, IL-6 trans-signaling-driven emphysematous changes in the lung correlated with mechanistic target of rapamycin complex 1 hyperactivation, and treatment of emphysema mouse models with the mechanistic target of rapamycin complex 1 inhibitor rapamycin attenuated emphysematous changes. Conclusions: Collectively, our data reveal that specific targeting of IL-6 trans-signaling may represent a novel treatment strategy for emphysema.",
keywords = "Interleukin-6, Mechanistic target of rapamycin complex 1, Mouse models, Pulmonary emphysema, Trans-signaling",
author = "Ruwanpura, {Saleela M.} and Louise McLeod and Dousha, {Lovisa F.} and Seow, {Huei Jiunn} and Sultan Alhayyani and Tate, {Michelle D.} and Virginie Deswaerte and Brooks, {Gavin D.} and Steven Bozinovski and Martin MacDonald and Christoph Garbers and King, {Paul T.} and Bardin, {Philip G.} and Ross Vlahos and Stefan Rose-John and Anderson, {Gary P.} and Jenkins, {Brendan J.}",
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Therapeutic targeting of the IL-6 trans-signaling/mechanistic target of rapamycin complex 1 axis in pulmonary emphysema. / Ruwanpura, Saleela M.; McLeod, Louise; Dousha, Lovisa F.; Seow, Huei Jiunn; Alhayyani, Sultan; Tate, Michelle D.; Deswaerte, Virginie; Brooks, Gavin D.; Bozinovski, Steven; MacDonald, Martin; Garbers, Christoph; King, Paul T.; Bardin, Philip G.; Vlahos, Ross; Rose-John, Stefan; Anderson, Gary P.; Jenkins, Brendan J.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 194, No. 12, 15.12.2016, p. 1494-1505.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Therapeutic targeting of the IL-6 trans-signaling/mechanistic target of rapamycin complex 1 axis in pulmonary emphysema

AU - Ruwanpura, Saleela M.

AU - McLeod, Louise

AU - Dousha, Lovisa F.

AU - Seow, Huei Jiunn

AU - Alhayyani, Sultan

AU - Tate, Michelle D.

AU - Deswaerte, Virginie

AU - Brooks, Gavin D.

AU - Bozinovski, Steven

AU - MacDonald, Martin

AU - Garbers, Christoph

AU - King, Paul T.

AU - Bardin, Philip G.

AU - Vlahos, Ross

AU - Rose-John, Stefan

AU - Anderson, Gary P.

AU - Jenkins, Brendan J.

PY - 2016/12/15

Y1 - 2016/12/15

N2 - Rationale: The potent immunomodulatory cytokine IL-6 is consistently up-regulated in human lungs with emphysema and in mouse emphysema models; however, the mechanisms by which IL-6 promotes emphysema remain obscure. IL-6 signals using two distinct modes: classical signaling via its membrane-bound IL-6 receptor (IL-6R), and trans-signaling via a naturally occurring soluble IL-6R. Objectives: To identify whether IL-6 trans-signaling and/or classical signaling contribute to the pathogenesis of emphysema. Methods: We used the gp130F/F genetic mouse model for spontaneous emphysema and cigarette smoke-induced emphysema models. Emphysema in mice was quantified by various methods including in vivo lung function and stereology, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to assess alveolar cell apoptosis. In mouse and human lung tissues, the expression level and location of IL-6 signaling-related genes and proteinsweremeasured, and the levels of IL-6 and related proteins in sera from emphysematous mice and patients were also assessed. Measurements and Main Results: Lung tissues from patients with emphysema, and from spontaneous and cigarette smoke-induced emphysema mouse models, were characterized by excessive production of soluble IL-6R. Genetic blockade of IL-6 trans-signaling in emphysema mouse models and therapy with the IL-6 trans-signaling antagonist sgp130Fc ameliorated emphysema by suppressing augmented alveolar type II cell apoptosis. Furthermore, IL-6 trans-signaling-driven emphysematous changes in the lung correlated with mechanistic target of rapamycin complex 1 hyperactivation, and treatment of emphysema mouse models with the mechanistic target of rapamycin complex 1 inhibitor rapamycin attenuated emphysematous changes. Conclusions: Collectively, our data reveal that specific targeting of IL-6 trans-signaling may represent a novel treatment strategy for emphysema.

AB - Rationale: The potent immunomodulatory cytokine IL-6 is consistently up-regulated in human lungs with emphysema and in mouse emphysema models; however, the mechanisms by which IL-6 promotes emphysema remain obscure. IL-6 signals using two distinct modes: classical signaling via its membrane-bound IL-6 receptor (IL-6R), and trans-signaling via a naturally occurring soluble IL-6R. Objectives: To identify whether IL-6 trans-signaling and/or classical signaling contribute to the pathogenesis of emphysema. Methods: We used the gp130F/F genetic mouse model for spontaneous emphysema and cigarette smoke-induced emphysema models. Emphysema in mice was quantified by various methods including in vivo lung function and stereology, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to assess alveolar cell apoptosis. In mouse and human lung tissues, the expression level and location of IL-6 signaling-related genes and proteinsweremeasured, and the levels of IL-6 and related proteins in sera from emphysematous mice and patients were also assessed. Measurements and Main Results: Lung tissues from patients with emphysema, and from spontaneous and cigarette smoke-induced emphysema mouse models, were characterized by excessive production of soluble IL-6R. Genetic blockade of IL-6 trans-signaling in emphysema mouse models and therapy with the IL-6 trans-signaling antagonist sgp130Fc ameliorated emphysema by suppressing augmented alveolar type II cell apoptosis. Furthermore, IL-6 trans-signaling-driven emphysematous changes in the lung correlated with mechanistic target of rapamycin complex 1 hyperactivation, and treatment of emphysema mouse models with the mechanistic target of rapamycin complex 1 inhibitor rapamycin attenuated emphysematous changes. Conclusions: Collectively, our data reveal that specific targeting of IL-6 trans-signaling may represent a novel treatment strategy for emphysema.

KW - Interleukin-6

KW - Mechanistic target of rapamycin complex 1

KW - Mouse models

KW - Pulmonary emphysema

KW - Trans-signaling

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U2 - 10.1164/rccm.201512-2368OC

DO - 10.1164/rccm.201512-2368OC

M3 - Article

VL - 194

SP - 1494

EP - 1505

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

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ER -