Increased systemic and pulmonary levels of IL-6 (interleukin-6) are associated with the severity of exacerbations and decline of lung function in patients with COPD (chronic obstructive pulmonary disease). Whether IL-6 is directly involved or plays a bystander role in the pathophysiology of COPD remains unclear. Here we hypothesized that neutralizing circulating levels of IL-6 would modulate episodes of acute pulmonary inflammation following CS (cigarette smoke) exposure and virus-like challenges. For this purpose, we used a model where C57BL/6 mice were exposed to CS twice daily via a nose-only system, and concomitant periodic intranasal challenge with poly(I:C), a synthetic ligand for TLR3 (Toll-like receptor 3) that mimics the encounter with double stranded RNA that is carried by influenza-like viruses. This protocol recapitulates several aspects of acute pulmonary inflammation associated with COPD, including prominent airway neutrophilia, insensitivity to steroid treatment and increased levels of several inflammatory cytokines in BAL (bronchoalveolar lavage) samples. Although IL-6-deficient mice exposed to CS/poly(I:C) developed pulmonary inflammation similar to WT (wild-type) controls, WT mice exposed to CS/poly(I:C) and treated intraperitoneally with IL-6-neutralizing antibodies showed significantly lower blood counts of lymphocytes and monocytes, lower BAL levels of IL-6 and CXCL1 (CXC chemokine ligand 1)/KC (keratinocyte chemoattractant), as well as reduced numbers of BAL neutrophils, lymphocytes and macrophages. Our results thus indicate that the systemic neutralization of IL-6 significantly reduces CS/poly(I:C)-induced pulmonary inflammation, which may be a relevant approach to the treatment of episodes of acute pulmonary inflammation associated with COPD.
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Research Article|
July 16 2013
Interleukin-6 neutralization alleviates pulmonary inflammation in mice exposed to cigarette smoke and poly(I:C)
Cedric Hubeau;
*Inflammation and Remodeling Research Unit, Pfizer Worldwide Research and Development, 200 Cambridgepark Drive, Cambridge, MA 02140, U.S.A.
Correspondence: Dr Cedric Hubeau (email [email protected]).
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John E. Kubera;
John E. Kubera
*Inflammation and Remodeling Research Unit, Pfizer Worldwide Research and Development, 200 Cambridgepark Drive, Cambridge, MA 02140, U.S.A.
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Katherine Masek-Hammerman;
Katherine Masek-Hammerman
†Drug Safety Research and Development, Pfizer Worldwide Research and Development, 200 Cambridgepark Drive, Cambridge, MA 02140, U.S.A.
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Cara M. M. Williams
Cara M. M. Williams
*Inflammation and Remodeling Research Unit, Pfizer Worldwide Research and Development, 200 Cambridgepark Drive, Cambridge, MA 02140, U.S.A.
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Publisher: Portland Press Ltd
Received:
March 01 2013
Revision Received:
May 29 2013
Accepted:
June 05 2013
Accepted Manuscript online:
June 05 2013
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2013 Biochemical Society
2013
Clin Sci (Lond) (2013) 125 (10): 483–493.
Article history
Received:
March 01 2013
Revision Received:
May 29 2013
Accepted:
June 05 2013
Accepted Manuscript online:
June 05 2013
Citation
Cedric Hubeau, John E. Kubera, Katherine Masek-Hammerman, Cara M. M. Williams; Interleukin-6 neutralization alleviates pulmonary inflammation in mice exposed to cigarette smoke and poly(I:C). Clin Sci (Lond) 1 November 2013; 125 (10): 483–493. doi: https://doi.org/10.1042/CS20130110
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