The IL6R variation Asp358Ala is a potential modifier of lung function in subjects with asthma

Hawkins, Gregory A.; Robinson, Mac; Hastie, Annette T.; Li, Xingnan; Li, Huashi; Moore, Wendy C.; Howard, Timothy D.; Busse, William W.; Erzurum, Serpil C.; Wenzel, Sally E.; Peters, Stephen P.; Meyers, Deborah A.; Bleecker, Eugene R.

doi:10.1016/j.jaci.2012.03.018

Cited by 84 publications

(79 citation statements)

References 23 publications

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“…For example, single nucleotide polymorphisms in the interleukin (IL)-4 receptor-a specifically associate with persistent airways inflammation, severe asthma exacerbations and submucosal mast cells supporting functional alterations in the IL-4 pathway influencing allergic inflammation in some severe asthmatics [19]. Another recent paper showed that variation in IL-6 receptor associated with lower lung function and more severe asthma subphenotypes suggesting another therapeutic target [38]. Finally, there is evidence that genetic variation in a number of genes may interact and influence lung function, asthma susceptibility and severity [39].…”

Section: Genetics and Epigeneticsmentioning

confidence: 99%

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

et al. 2013

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Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults.A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations.When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided.Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

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Section: Genetics and Epigeneticsmentioning

confidence: 99%

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

et al. 2013

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“…S3C). Interestingly, site-specific O-glycosylation appears to play a role in coregulating both variants and the change in IL6-RA signaling caused by the D358A SNV has been suggested to have a pathogenic role in asthma and is associated with more severe disease (45). Finally, an experimental mutation in ErbB4 in close proximity to the glycosylation sites identified here has previously been shown to result in a marked increase in signaling (27).…”

Section: Congenital Gene Variants With Potential Dysregulated Ectodomainmentioning

confidence: 69%

“…Recombinant glycosyltransferases were expressed as soluble secreted truncated proteins in insect cells (45). In vitro activity assays for GalNAc-T glycosylation of peptides (Schafer-N, NeoBioSci) were performed as described and monitored with MALDI-TOF (20).…”

Section: Methodsmentioning

confidence: 99%

A systematic study of modulation of ADAM-mediated ectodomain shedding by site-specific O-glycosylation

Goth

Halim

Khetarpal

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

112

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Regulated shedding of the ectodomain of cell membrane proteins by proteases is a common process that releases the extracellular domain from the cell and activates cell signaling. Ectodomain shedding occurs in the immediate extracellular juxtamembrane region, which is also where O-glycosylation is often found and examples of crosstalk between shedding and O-glycosylation have been reported. Here, we systematically investigated the potential of site-specific O-glycosylation mediated by distinct polypeptide GalNAc-transferase (GalNAc-T) isoforms to coregulate ectodomain shedding mediated by the A Disintegrin And Metalloproteinase (ADAM) subfamily of proteases and in particular ADAM17. We analyzed 25 membrane proteins that are known to undergo ADAM17 shedding and where the processing sites included Ser/ Thr residues within ± 4 residues that could represent O-glycosites. We used in vitro GalNAc-T enzyme and ADAM cleavage assays to demonstrate that shedding of at least 12 of these proteins are potentially coregulated by O-glycosylation. Using TNF-α as an example, we confirmed that shedding mediated by ADAM17 is coregulated by O-glycosylation controlled by the GalNAc-T2 isoform both ex vivo in isogenic cell models and in vivo in mouse Galnt2 knockouts. The study provides compelling evidence for a wider role of site-specific O-glycosylation in ectodomain shedding.

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“…Unlike classical IL-6 signaling that binds to the membrane-bound IL-6 receptor to activate Jak/Stat pathways, IL-6 trans-signaling is an extracellular process that involves binding of IL-6 to a soluble form of the IL-6 receptor, which forms a complex that can then regulate classical IL-6 signaling and can alter Jak/Stat signaling in cells that do not express the IL-6 receptor (35). IL-6 trans-signaling has been implicated in severe asthma (20), and upregulation of HILDPA in ASM cells suggests it has a role in airway remodeling in asthma. Downregulation of both ANGPTL4 and HILDPA in vitamin D-deficient mice provides potential mechanisms that may contribute to the reduced ASM mass in airways of these mice, although we did not directly test this, and further studies are required.…”

Section: Discussionmentioning

confidence: 99%

Identification of genes differentially regulated by vitamin D deficiency that alter lung pathophysiology and inflammation in allergic airways disease

Foong

Bosco

Troy

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Vitamin D deficiency is associated with asthma risk. Vitamin D deficiency may enhance the inflammatory response, and we have previously shown that airway remodeling and airway hyperresponsiveness is increased in vitamin D-deficient mice. In this study, we hypothesize that vitamin D deficiency would exacerbate house dust mite (HDM)-induced inflammation and alterations in lung structure and function. A BALB/c mouse model of vitamin D deficiency was established by dietary manipulation. Responsiveness to methacholine, airway smooth muscle (ASM) mass, mucus cell metaplasia, lung and airway inflammation, and cytokines in bronchoalveolar lavage (BAL) fluid were assessed. Gene expression patterns in mouse lung samples were profiled by RNA-Seq. HDM exposure increased inflammation and inflammatory cytokines in BAL, baseline airway resistance, tissue elastance, and ASM mass. Vitamin D deficiency enhanced the HDM-induced influx of lymphocytes into BAL, ameliorated the HDM-induced increase in ASM mass, and protected against the HDM-induced increase in baseline airway resistance. RNA-Seq identified nine genes that were differentially regulated by vitamin D deficiency in the lungs of HDM-treated mice. Immunohistochemical staining confirmed that protein expression of midline 1 (MID1) and adrenomedullin was differentially regulated such that they promoted inflammation, while hypoxia-inducible lipid dropletassociated, which is associated with ASM remodeling, was downregulated. Protein expression studies in human bronchial epithelial cells also showed that addition of vitamin D decreased MID1 expression. Differential regulation of these genes by vitamin D deficiency could determine lung inflammation and pathophysiology and suggest that the effect of vitamin D deficiency on HDM-induced allergic airways disease is complex. airway remodeling; airway hyperresponsiveness; mouse model; RNASeq; house dust mite VITAMIN D DEFICIENCY IS PREVALENT all over the world and is a public health concern. Epidemiological studies have linked vitamin D deficiency to respiratory diseases, including lung cancer, chronic obstructive pulmonary disease, and asthma (16,26,43). However, while there is evidence that higher vitamin D levels may reduce the risk of asthma exacerbations, there is inconclusive evidence that vitamin D deficiency has the capacity to cause asthma (5,13,34).Asthma is an inflammatory disorder affecting the conducting airways (22). Allergic asthma is characterized by T helper (Th) 2 type inflammation, and persistent airway inflammation drives structural alterations in the lung (32). These structural changes, termed airway remodeling, lead to reversible airflow obstruction, deficits in lung function, and airway hyperresponsiveness (AHR) (32). These functional deficits are ultimately linked to asthma-related morbidity. Vitamin D has important immunomodulatory properties, as evidenced by the widespread expression of the vitamin D receptor on immune cells, including activated T and B cells, macrophages, and dendritic cells (18). Studies hav...

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The IL6R variation Asp358Ala is a potential modifier of lung function in subjects with asthma

Cited by 84 publications

References 23 publications

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

A systematic study of modulation of ADAM-mediated ectodomain shedding by site-specific O-glycosylation

Identification of genes differentially regulated by vitamin D deficiency that alter lung pathophysiology and inflammation in allergic airways disease

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