Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion

Nanzer, AM; Chambers, Emma S.; Ryanna, Kimuli; Richards, David F.; Black, Cheryl; Timms, Philip; Martineau, Adrian R.; Griffiths, Christopher J.; Corrigan, Christopher; Hawrylowicz, Catherine M.

doi:10.1016/j.jaci.2013.03.037

Cited by 167 publications

(167 citation statements)

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“…Inactivation of protease activity led to reduction in allergic parameters. These results demonstrate that proteolytic activity of Per a 10 potentiates its allergenicity.There was an increase in levels of IL-17A in the sputum of severe asthmatics [23] and may act as a marker and risk factor for severe asthma [24]. Previously, it was shown that GC frass induces IL-17A secretion in a PAR-2-dependent manner.…”

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confidence: 89%

Protease activity of Per a 10 potentiates Th2 polarization by increasing IL‐23 and OX40L

2015

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Proteases are implicated in exacerbation of allergic diseases. In this study, the role of proteolytic activity of Per a 10 was evaluated on Th2 polarization. Intranasal administration of Per a 10 in mice led to allergic airway inflammation as seen by higher IgE levels, cellular infiltration, IL-17A, and Th2 cytokines, whereas, inactive ( )Per a 10 showed attenuated response. There was an increased OX40L expression on lung and lymph node dendritic cells in Per a 10 immunized group and on Per a 10 stimulated BMDCs. Reduction in CD40 expression without any change at transcript level in lungs of Per a 10 immunized mice suggested CD40 cleavage. BMDCs pulsed with Per a 10 showed reduced CD40 expression with lower IL-12p70 secretion as compared to heat inactivated Per a 10. IL-23, TNF-α, and IL-6 levels were significantly higher in Per a 10 stimulated BMDCs supernatant. In DC-T cell coculture studies, Per a 10 pulsed BMDCs showed higher levels of IL-4 and IL-13 that were reduced on blocking of either IL-23 or OX40L. In conclusion, the data suggests a critical role of protease activity of Per a 10 in promoting Th2 polarization by increasing IL-23 secretion and OX40L expression on dendritic cells.Keywords: CD40 r Cytokines r Dendritic cell r OX40L r Protease allergen Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionProteases are known to play an important role in manifestation of diseases like cancer, coagulopathies, respiratory inflammatory diseases, rheumatoid arthritis, and degenerative diseases [1][2][3]. Proteases from sources like house dust mite (Der p 1, Der p 3, Der p 6, Der p 9, Der f 1) and fungi (Asp f 13, Pen c 1, Pen c 13, Epi p 1) have been characterized as potent allergens [4]. Protease allergens act by proteolytic cleavage of an array of cell surface molecules and are known to modulate the functions of a variety of cell types including both immune and structural cells [5]. Proteolytic allergens from house dust mite are known to exacerbate allergic immune responses by selective cleavage of CD23, CD25, DC-SIGN, and DC-SIGNR on surface of immune cells Correspondence: Dr. Naveen Arora e-mail: naveen@igib.res.in; navdelhi@hotmail.com [6,7]. Further, cleavage and subsequent activation of PAR receptors by proteases lead to increased secretion of chemokines, proinflammatory, and pro Th2 cytokines from airway epithelial cells [8,9]. Studies have reported impaired epithelial barrier function as the feature of allergic diseases like asthma and atopic dermatitis [10]. The enzymatic activity of proteases has been reported to compromise epithelial barrier directly by cleaving tight junction proteins ZO-1 and occludin thereby increasing epithelial permeability [11,12]. Proteases can also act as adjuvants to bystander allergens present in the same microenvironment [13,14].Cockroaches have emerged as an important source of indoor allergens worldwide and cockroach extract is shown to be rich in proteases [15]. Previously, Per a 10, a serine protea...

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Protease activity of Per a 10 potentiates Th2 polarization by increasing IL‐23 and OX40L

2015

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“…From a mechanistic point-of-view, it is interesting that ZHAO et al [45] were able to demonstrate a positive correlation between IL-17A and IL-23 protein in the group of patients with allergic asthma, since this is compatible with IL-23 constituting a trigger of IL-17A production in circulating Th17 cells. In a recently published study on blood Th cells from healthy control subjects and patients with moderateto-severe asthma who had been without treatment with glucocorticoids for 4 weeks, NANZER et al [46] found that the intracellular immunoreactivity for IL-17A and IL-22 was enhanced in patients with ''steroidrefractory'' but not ''steroid-sensitive'' clinical disease. The blood Th cells co-expressing IL-17A and IL-22 were enhanced in all patients with asthma, as was the corresponding release of extracellular protein in vitro.…”

Section: Systemic Involvementmentioning

confidence: 99%

Interleukin-17 cytokine signalling in patients with asthma

Lindén

Dahlén

2014

Eur Respir J

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Asthma remains a global health problem and, therefore, more effective pharmacotherapy is needed. This is particularly true for chronic and severe asthma. In these clinical phenotypes, chronic inflammation involving neutrophils is likely to play a pathogenic role, making it interesting to target cytokine signalling involved in the accumulation of neutrophils. Therefore, it is of interest that the archetype T-helper 17 cell cytokine interleukin (IL)-17A, perhaps also IL-17F, controls neutrophil accumulation, mucus secretion, macrophage mobilisation and smooth muscle reactivity in various experimental airway models. However, much less is known about the involvement of signalling via IL-17 cytokines in humans with asthma. Existing evidence suggests that these cytokines are released from several types of immune cells in asthma and, for IL-17A, there is a local increase associated with disease severity, with the mobilisation of neutrophils and smooth muscle cells locally in the airways. Even though the causative role of IL-17 cytokines remains unclear, there is potential for clinical utility in targeting IL-17A specifically in patients with moderate-to-severe asthma and high reversibility. There is a need for new and well-powered clinical investigations of signalling via IL-17 cytokines in this clinical phenotype. @ERSpublications There is potential utility for drugs targeting IL-17 cytokine signalling in a sub-group of patients with asthma

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“…However, in the absence of such a premorbid abnormality in steroid signaling there is no unifying explanation of the SR phenotype. Candidate mechanisms include overexpression of the inhibitory β-isoform of the GR (GR-β) (1,5), but there is also increasing evidence to suggest that specific variations in the adaptive immune response to glucocorticoid therapy play a key role (6)(7)(8).…”

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Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A

Schewitz-Bowers

Lait

Copland

et al. 2015

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

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Glucocorticoids remain the cornerstone of treatment for inflammatory conditions, but their utility is limited by a plethora of side effects. One of the key goals of immunotherapy across medical disciplines is to minimize patients’ glucocorticoid use. Increasing evidence suggests that variations in the adaptive immune response play a critical role in defining the dose of glucocorticoids required to control an individual’s disease, and Th17 cells are strong candidate drivers for nonresponsiveness [also called steroid resistance (SR)]. Here we use gene-expression profiling to further characterize the SR phenotype in T cells and show that Th17 cells generated from both SR and steroid-sensitive individuals exhibit restricted genome-wide responses to glucocorticoids in vitro, and that this is independent of glucocorticoid receptor translocation or isoform expression. In addition, we demonstrate, both in transgenic murine T cells in vitro and in an in vivo murine model of autoimmunity, that Th17 cells are reciprocally sensitive to suppression with the calcineurin inhibitor, cyclosporine A. This result was replicated in human Th17 cells in vitro, which were found to have a conversely large genome-wide shift in response to cyclosporine A. These observations suggest that the clinical efficacy of cyclosporine A in the treatment of SR diseases may be because of its selective attenuation of Th17 cells, and also that novel therapeutics, which target either Th17 cells themselves or the effector memory T-helper cell population from which they are derived, would be strong candidates for drug development in the context of SR inflammation.

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Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion

Cited by 167 publications

References 49 publications

Protease activity of Per a 10 potentiates Th2 polarization by increasing IL‐23 and OX40L

Protease activity of Per a 10 potentiates Th2 polarization by increasing IL‐23 and OX40L

Interleukin-17 cytokine signalling in patients with asthma

Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A

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