Antiapoptotic serine protease inhibitors contribute to survival of allergenic T H 2 cells

Shamji, Mohamed H.; Temblay, Jeff N.; Cheng, Wei; Byrne, Susan; Macfarlane, Ellen; Switzer, Amy; Francisco, Natalia D.C.; Olexandra, Fedina; Jacubczik, Fabian; Durham, Stephen R.; Ashton‐Rickardt, Philip G.

doi:10.1016/j.jaci.2017.07.055

Cited by 16 publications

(18 citation statements)

References 55 publications

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“…This method has been published by others studying functional human immune responses, [32][33][34] and showed a similar degree of variability in IL-2 and tumor necrosis factor α production, whether cytokines levels were corrected for total cell numbers or not. 34 In our in vitro system, we empirically developed a model of high and low IL-2 based on typical concentrations used for Th2 cell cultures 10,37 as well as functional readouts of resistance/susceptibility to GC-induced apoptosis. Concentrations were lower than observed after ex vivo mitogenic activation of patients' cells, but similar to levels found to be produced from in vivo antigen-activated T cells 64 and BAL lymphocytes activated using beads coated with αCD2/CD3/CD28 13 and so may be more physiologically relevant.…”

Section: Discussionmentioning

confidence: 99%

“…Th2 cells are allergen‐specific memory T cells that circulate between the lymph nodes and periphery and as such can rapidly infiltrate tissues upon allergen exposure . While both cell types contribute to overall type 2 cytokine levels, the immunologic memory provided by Th2 cells is considered to mediate the persistent nature of allergic inflammation …”

Section: Introductionmentioning

confidence: 99%

“…[7][8][9] While both cell types contribute to overall type 2 cytokine levels, the immunologic memory provided by Th2 cells is considered to mediate the persistent nature of allergic inflammation. 8,10 Glucocorticoids (GCs) are the main treatment for asthma. 11 Their efficacy is considered, in large part, to be due to their ability to suppress type 2 cytokines, in vivo, 12 ex vivo 13 and in vitro.…”

Section: Introductionmentioning

confidence: 99%

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IL‐2 modulates Th2 cell responses to glucocorticosteroid: A cause of persistent type 2 inflammation?

Kanagalingam

Solomon

Vijeyakumaran

et al. 2019

Immunity Inflam & Disease

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Background Glucocorticosteroids (GCs) are the main treatment for asthma as they reduce type 2 cytokine expression and induce apoptosis. Asthma severity is associated with type 2 inflammation, circulating Th2 cells and higher GC requirements. Objective The aim of this study was to assess whether ex vivo production of interleukin 2 (IL‐2), a T‐cell survival factor, associated with clinical features of asthma severity, the proportion of blood Th2 cells and Th2 cell responses to GC. Methods Peripheral blood from asthma patients (n = 18) was obtained and the proportion of Th2 cells determined by flow cytometry. Peripheral blood cells were activated with mitogen (24 hours) and supernatant levels of IL‐2 and IL‐13 measured by enzyme‐linked immunosorbent assay. In vitro differentiated Th2 cells were treated with dexamethasone (DEX) and IL‐2 and assessed for apoptosis by flow cytometry (annexin V). Level of messenger RNA (mRNA) for antiapoptotic (BCL‐2) and proapoptotic (BIM) genes, IL‐13, GC receptor (GR) and FKBP5 were determined by quantitative real‐time polymerase chain reaction. GR binding was assessed by chromatin immunoprecipitation. Results IL‐2 produced by activated peripheral blood cells correlated negatively with lung function and positively with a daily dose of inhaled GC. When patients were stratified based on IL‐2 level, high IL‐2 producers made more IL‐13 and had a higher proportion of circulating Th2 cells. In vitro, increasing the level of IL‐2 in the culture media was associated with resistance to DEX‐induced apoptosis, with more BCL‐2/less BIM mRNA. Th2 cells cultured in high IL‐2 had more IL‐13, less GR mRNA, showed reduced binding of the GR to FKBP5, a known GC‐induced gene, and required higher concentrations of DEX for cytokine suppression. Conclusions and Clinical Relevance IL‐2 downregulates Th2 cell responses to GC, supporting both their survival and pro‐inflammatory capacity. These results suggest that a patient's potential to produce IL‐2 may be a determinant in asthma severity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

IL‐2 modulates Th2 cell responses to glucocorticosteroid: A cause of persistent type 2 inflammation?

Kanagalingam

Solomon

Vijeyakumaran

et al. 2019

Immunity Inflam & Disease

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“…4C), though this difference was not observed at higher DEX concentrations. 13 To assess the durability of GC suppression following activation, Th2 cells were pretreated with DEX (24hours), washed and activated with mitogen in the presence or absence of DEX (24hours) and high IL-2. Th2 cells receiving DEX as both a pre-treatment and during activation exhibited almost complete suppression of IL-13 mRNA (88 and 96%, respectively), while cells receiving DEX only as a pre-treatment had substantially more IL-13 mRNA following activation (Fig.…”

Section: The Il-2-gc Axis Regulates Suppression Of Type 2 Cytokinesmentioning

confidence: 99%

“…While both cell types contribute to overall type 2 cytokine levels, Th2 cells are considered the principle cell population responsible for their rapid release upon allergen re-exposure as well as maintenance of chronic allergic inflammation (11,13).…”

Section: Introductionmentioning

confidence: 99%

IL-2 Modulates Th2 cell Responses to Glucocorticoid: A Cause of Persistent Type 2 Inflammation?

Kanagalingam

Vijeyakumaran

Palikhe

et al. 2018

Preprint

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BackgroundInhaled glucocorticosteroids (GCs) are the main treatment for asthma as they reduce type 2 cytokine (IL-4, IL-5 and IL-13) expression and induce apoptosis. Asthma severity is associated with GC insensitivity, increased type 2 inflammation and circulating Th2 cells. Since IL-2 is a T cell survival factor, we assessed whether IL-2 levels associate with the proportion of Th2 cells and/or correlate with clinical features of asthma severity.MethodsPeripheral blood from asthma patients (n=18) was obtained and Th2 cell numbers determined by flow cytometry. Peripheral blood cells were activated with mitogen (24hrs) and supernatant levels of IL-2 and IL-13 measured by ELISA. In vitro differentiated Th2 cells were treated with dexamethasone and IL-2 and assessed for apoptosis by flow cytometry staining of Annexin V. Level of mRNA for anti-apoptotic (BCL-2) and pro-apoptotic (BIM) genes as well as IL-13 were determined by qRT-PCR.ResultsIL-2 produced by activated peripheral blood cells correlated negatively with lung function (FEV1) and positively with daily dose of inhaled GC. When patients were stratified based on IL-2 level, high IL-2 producers made more IL-13 and had more circulating Th2 cells. In vitro, increasing the level of IL-2 in the culture media was associated with resistance to DEX-induced apoptosis, more BCL-2 and less BIM mRNA. Th2 cells cultured with higher IL-2 also had more IL-13 mRNA and required higher concentrations of DEX for cytokine suppression.Conclusions and Clinical RelevanceIL-2 modulates Th2 cell responses to GC, supporting both their survival and pro-inflammatory capacity, suggesting that a patient’s potential to produce IL-2 may be a determinant in asthma severity.

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N6-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice

Wang

Ding

et al. 2023

Nat Commun

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Bacteria-triggered sepsis is characterized by systemic, uncontrolled inflammation in affected individuals. Controlling the excessive production of pro-inflammatory cytokines and subsequent organ dysfunction in sepsis remains challenging. Here, we demonstrate that Spi2a upregulation in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages reduces the production of pro-inflammatory cytokines and myocardial impairment. In addition, exposure to LPS upregulates the lysine acetyltransferase, KAT2B, to promote METTL14 protein stability through acetylation at K398, leading to the increased m6A methylation of Spi2a in macrophages. m6A-methylated Spi2a directly binds to IKKβ to impair IKK complex formation and inactivate the NF-κB pathway. The loss of m6A methylation in macrophages aggravates cytokine production and myocardial damage in mice under septic conditions, whereas forced expression of Spi2a reverses this phenotype. In septic patients, the mRNA expression levels of the human orthologue SERPINA3 negatively correlates with those of the cytokines, TNF, IL-6, IL-1β and IFNγ. Altogether, these findings suggest that m6A methylation of Spi2a negatively regulates macrophage activation in the context of sepsis.

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Antiapoptotic serine protease inhibitors contribute to survival of allergenic T H 2 cells

Abstract: The Serpins Spi2A in mice and SERPINB3 and SERPINB4 in allergic patients control the viability of T2 cells. This provides proof of principle for a therapeutic approach for allergic disease through ablation of allergic memory T2 cells through SERPINB3 and SERPINB4 mRNA downregulation.

Cited by 16 publications

References 55 publications

IL‐2 modulates Th2 cell responses to glucocorticosteroid: A cause of persistent type 2 inflammation?

IL‐2 modulates Th2 cell responses to glucocorticosteroid: A cause of persistent type 2 inflammation?

IL-2 Modulates Th2 cell Responses to Glucocorticoid: A Cause of Persistent Type 2 Inflammation?

N6-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice

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