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      Role of IL-6 in Asthma and Other Inflammatory Pulmonary Diseases

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          Abstract

          The incidence and severity of chronic lung diseases is growing and affects between 100 and 150 million people worldwide and is associated with a significant rate of mortality. Unfortunately, the initial cause that triggers most chronic lung diseases remains unknown and current available therapies only ameliorate, but do not cure the disease. Thus, there is a need for identification of new targets and development of novel therapies especially for those most severely affected. IL-6, like other inflammatory cytokines, has been shown to be elevated in different lung diseases, but it was considered a byproduct of ongoing inflammation in the lung. However, recent studies support a dissociation of IL-6 from inflammation in the lung and suggest that this cytokine plays an active role in pathogenesis of asthma and, in all likelihood, COPD. IL-6 may therefore be a germane target for treatment of these and other chronic lung disease. Here, we provide an overview of the studies in mouse models and human patients that provide support for the involvement of IL-6 in lung diseases.

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          Most cited references65

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          TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.

          We describe de novo generation of IL-17-producing T cells from naive CD4 T cells, induced in cocultures of naive CD4 T cells and naturally occurring CD4+ CD25+ T cells (Treg) in the presence of TLR3, TLR4, or TLR9 stimuli. Treg can be substituted by TGFbeta1, which, together with the proinflammatory cytokine IL-6, supports the differentiation of IL-17-producing T cells, a process that is amplified by IL-1beta and TNFalpha. We could not detect a role for IL-23 in the differentiation of IL-17-producing T cells but confirmed its importance for their survival and expansion. Transcription factors GATA-3 and T-bet, as well as its target Hlx, are absent in IL-17-producing T cells, and they do not express the negative regulator for TGFbeta signaling, Smad7. Our data indicate that, in the presence of IL-6, TGFbeta1 subverts Th1 and Th2 differentiation for the generation of IL-17-producing T cells.
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            Generation of Pathogenic Th17 Cells in the Absence of TGF-β Signaling

            CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity 1–4 . Crucial for T helper17 (Th17) cells in vivo 5,6 , IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been argued to be the factors responsible for initiating specification 7–10 . Herein, we show that Th17 differentiation can occur in the absence of TGF-β signaling. Neither IL-6 nor IL-23 alone efficiently generated Th17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naïve precursors, independently of TGF-β. Epigenetic modification of the Il17a/Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed Rorγt and T-bet. T-bet+ Rorγt+ Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data suggest an alternative mode for Th17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore have may have therapeutic implications.
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              Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production.

              Interleukin (IL)-13 is a pleiotropic cytokine produced in large quantities by activated CD4(+) Th2 lymphocytes. To define further its potential in vivo effector functions, the Clara cell 10-kDa protein promoter was used to express IL-13 selectively in the lung, and the phenotype of the resulting transgenic mice was characterized. In contrast to transgene-negative littermates, the lungs of transgene-positive mice contained an inflammatory response around small and large airways and in the surrounding parenchyma. It was mononuclear in nature and contained significant numbers of eosinophils and enlarged and occasionally multinucleated macrophages. Airway epithelial cell hypertrophy, mucus cell metaplasia, the hyperproduction of neutral and acidic mucus, the deposition of Charcot-Leyden-like crystals, and subepithelial airway fibrosis were also prominently noted. Eotaxin protein and mRNA were also present in large quantities in the lungs of the transgene-positive, but not the transgene-negative, mice. IL-4, IL-5, granulocyte-macrophage colony-stimulating factor, and monocyte chemoattractant protein-5 were not similarly detected. Physiological evaluations revealed significant increases in baseline airways resistance and airways hyperresponsiveness (AHR) to methacholine in transgene-positive animals. Thus, the targeted pulmonary expression of IL-13 causes a mononuclear and eosinophilic inflammatory response, mucus cell metaplasia, the deposition of Charcot-Leyden-like crystals, airway fibrosis, eotaxin production, airways obstruction, and nonspecific AHR. IL-13 may play an important role in the pathogenesis of similar responses in asthma or other Th2-polarized tissue responses.
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                Author and article information

                Journal
                Int J Biol Sci
                Int. J. Biol. Sci
                ijbs
                International Journal of Biological Sciences
                Ivyspring International Publisher (Sydney )
                1449-2288
                2012
                25 October 2012
                : 8
                : 9
                : 1281-1290
                Affiliations
                1. Department of Medicine, Immunobiology Division, University of Vermont, Burlington, VT 05405, USA;
                2. Pulmonary and Critical Care Medicine Division, University of Vermont, Burlington, VT 05405, USA.
                Author notes
                ✉ Corresponding author: Mercedes Rincon, Ph.D. Professor, Department of Medicine/Immunobiology, Given C331, University of Vermont, 89 Beaumont Ave., Burlington, VT 05405. Phone: 802-656.0937 Fax: 802-656-3854 mrincon@ 123456uvm.edu .

                Competing Interests: M. Rincon has acted as a consultant for Genentech regarding IL-6 signaling and its role in rheumatoid arthritis.

                Article
                ijbsv08p1281
                10.7150/ijbs.4874
                3491451
                23136556
                088dba27-0806-4fd6-9e2c-52bee8680ae4
                © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.
                History
                : 14 July 2012
                : 14 August 2012
                Categories
                Review

                Life sciences
                chronic lung diseases,il-6
                Life sciences
                chronic lung diseases, il-6

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