Glucocorticoid and TNF signaling converge at A20 (TNFAIP3) to repress airway smooth muscle cytokine expression

Sasse, Sarah K.; Altonsy, Mohammed O.; Kadiyala, Vineela; Cao, Gaoyuan; Panettieri, Reynold A.; Gerber, Anthony N.

doi:10.1152/ajplung.00179.2016

Cited by 24 publications

(35 citation statements)

References 69 publications

(70 reference statements)

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“…Although control virus had little or no effect on IL1B-induced inflammatory mRNA expression, many inflammatory mRNAs, including CCL4, CCL20, CSF2, CXCL1, CXCL3, CXCL5, IL8, PTGS2, and others, showed significant repression. This is consistent with prior observations (23,29). BIRC3, CCL2, CCL5, IFNGR1, IL6, LAMB3, MAP3K8, NFKB2, NFKBIZ, and TNFAIP3 mRNAs were induced by IL1B, but not significantly affected by DUSP1 overexpression ( Fig.…”

Section: Effect Of Dusp1 Overexpression On Inflammatory Genesupporting

confidence: 93%

“…transrepression, may account for this early effect on IRF1 transcription rate. This is supported by the data from BEAS-2B cells showing dexamethasone to reduce TNF-induced IRF1 expression (data not shown) in a manner that correlates with reduced binding of p65 (RELA) to the IRF1 promoter region (29). 3 However, irrespective of any GR transrepression, within 2 h post-treatment there was no effect of dexamethasone on IRF1 transcription.…”

Section: Negative Regulation Of Irf1 By Mapkssupporting

confidence: 58%

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DUSP1 Maintains IRF1 and Leads to Increased Expression of IRF1-dependent Genes

Shah

King

Mostafa

et al. 2016

Journal of Biological Chemistry

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Although the mitogen-activated protein kinase (MAPK) phosphatase, DUSP1, mediates dexamethasone-induced repression of MAPKs, 14 of 46 interleukin-1␤ (IL1B)-induced mRNAs were significantly enhanced by DUSP1 overexpression in pulmonary A549 cells. These include the interferon regulatory factor, IRF1, and the chemokine, CXCL10. Of these, DUSP1-enhanced mRNAs, 10 including CXCL10, were IRF1-dependent. MAPK inhibitors and DUSP1 overexpression prolonged IRF1 expression by elevating transcription and increasing IRF1 mRNA and protein stability. Conversely, DUSP1 silencing increased IL1B-induced MAPK phosphorylation while significantly reducing IRF1 protein expression at 4 h. This confirms a regulatory network whereby DUSP1 switches off MAPKs to maintain IRF1 expression. There was no repression of IRF1 expression by dexamethasone in primary human bronchial epithelial cells, and in A549 cells IL1B-induced IRF1 protein was only modestly and transiently repressed. Although dexamethasone did not repress IL1B-induced IRF1 protein expression at 4 -6 h, silencing of IL1B plus dexamethasone-induced DUSP1 significantly reduced IRF1 expression. IL1B-induced expression of CXCL10 was largely insensitive to dexamethasone, whereas other DUSP1-enhanced, IRF1-dependent mRNAs showed various degrees of repression. With IL1B plus dexamethasone, CXCL10 expression was also IRF1-dependent, and expression was reduced by DUSP1 silencing. Thus, IL1B plus dexamethasone-induced DUSP1 maintains expression of IRF1 and the IRF1-dependent gene, CXCL10. This is supported by chromatin immunoprecipitation showing IRF1 recruitment to be essentially unaffected by dexamethasone at the CXCL10 promoter or at the promoters of more highly repressed IRF1-dependent genes. Since IRF1-dependent genes, such as CXCL10, are central to host defense, these data may help explain the reduced effectiveness of glucocorticoids during asthma exacerbations.Inhaled glucocorticoids are referred to clinically as inhaled corticosteroids and bind to the glucocorticoid receptor (GR 2 ; NR3C1). These drugs suppress inflammatory gene expression and are a mainstay in the treatment of asthma (1). However, poor responsiveness to inhaled corticosteroid therapy by asthmatics with neutrophilic inflammation or viral infections and by individuals with chronic obstructive pulmonary disease (COPD) necessitates high, often oral, doses of glucocorticoid (1-3). This, if maintained over prolonged periods, may lead to contraindications, including osteoporosis, muscle wasting, increased blood glucose, weight gain, and suppression of the hypothalamic-pituitary-adrenal axis (4). Thus, an unmet clinical need exists to improve the therapeutic ratio of glucocorticoids in such disease situations.Airway epithelial cells release proinflammatory cytokines, chemokines, adhesion molecules, and inflammatory enzymes and play critical roles in asthma (5). Acting on the airway epithelium, glucocorticoids suppress the production of numerous epithelial-derived mediators, and this helps to reduce inflammatory cell re...

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Section: Effect Of Dusp1 Overexpression On Inflammatory Genesupporting

confidence: 93%

Section: Negative Regulation Of Irf1 By Mapkssupporting

confidence: 58%

DUSP1 Maintains IRF1 and Leads to Increased Expression of IRF1-dependent Genes

Shah

King

Mostafa

et al. 2016

Journal of Biological Chemistry

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“…An important anti‐inflammatory role for this ubiquitin has been reported in arthritis, auto‐immune diseases, cardiovascular diseases, cystic fibrosis, chronic obstructive pulmonary disease (COPD), allergies and asthma . In addition, the modulation of the expression of A20 has been demonstrated to be an important mechanism of action of certain drugs including methotrexate, quercetin and the combination of long‐acting β 2 ‐adrenoceptor agonistsand glucocorticoids . Moreover, it has recently been reported that there is a positive association between a polymorphism in the A20 gene and susceptibility to human asthma in the population investigated in the GABRIELA study, a study that focuses on the effects of farm environments on asthma and allergy in children from central Europe .…”

Section: Discussionmentioning

confidence: 99%

“…20,[27][28][29][30][31][32][33] In addition, the modulation of the expression of A20 has been demonstrated to be an important mechanism of action of certain drugs including methotrexate, quercetin and the combination of long-acting β 2 -adrenoceptor agonistsand glucocorticoids. [34][35][36][37] Moreover, it has recently been reported that there is a positive association between a polymorphism in the A20 gene and susceptibility to human asthma in the population investigated in the GABRIELA study, a study that focuses on the effects of farm environments on asthma and allergy in children from central Europe. 20 Furthermore, mRNA levels of A20 measured by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) were shown to be significantly reduced in epithelial cells obtained from subjects with mild or severe asthma when compared with healthy controls, findings confirmed with protein levels.…”

Section: This Disparity Between the Pharmacokinetic And Pharmacodynamicmentioning

confidence: 99%

Modulation of allergic inflammation in the lung by a peptide derived from Mycobacteria tuberculosis chaperonin 60.1

Riffo‐Vasquez

Kanabar

Keir

et al. 2020

Clin Experimental Allergy

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Background We have previously demonstrated that Mycobacteria tuberculosis chaperonin 60.1 inhibits leucocyte diapedesis and bronchial hyperresponsiveness in a murine model of allergic lung inflammation. Methods In the present study, we have investigated the effect of a shorter peptide sequence derived from Cpn 60.1, named IRL201104, on allergic lung inflammation induced by ovalbumin (OVA) in mice and by house dust mite (HDM) in guinea pigs, as well as investigating the action of IRL201104 on human cells in vitro. Results Pre‐treatment of mice or guinea pigs with IRL201104 inhibits the infiltration of eosinophils to the lung, cytokine release, and in guinea pig skin, inhibits allergen‐induced vascular permeability. The protective effect of intranasal IRL201104 against OVA‐induced eosinophilia persisted for up to 20 days post‐treatment. Moreover, OVA‐sensitized mice treated intranasally with 20 ng/kg of IRL201104 show a significant increase in the expression of the anti‐inflammatory molecule ubiquitin A20 and significant inhibition of the activation of NF‐κB in lung tissue. Our results also show that A20 expression was significantly reduced in blood leucocytes and ASM obtained from patients with asthma compared to cells obtained from healthy subjects which were restored after incubation with IRL201104 in vitro, when added alone, or in combination with LPS or TNF‐α in ASM. Conclusions Our results suggest that a peptide derived from mycobacterial Cpn60.1 has a long‐lasting anti‐inflammatory and immunomodulatory activity which may help explain some of the protective effects of TB against allergic diseases.

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“…2A). However, unlike glucocorticoid-repressed, NF-B-dependent mRNAs, such as IL8 or CSF2 (GM-CSF), TNFAIP3 expression, as induced by pro-inflammatory stimuli, is maintained or enhanced with the addition of glucocorticoid (11,48,49) (Fig. 1).…”

Section: Glucocorticoids Maintain and Enhance Feedback Controlmentioning

confidence: 99%

Glucocorticoid and cytokine crosstalk: Feedback, feedforward, and co-regulatory interactions determine repression or resistance

Newton

Shah

Altonsy

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillInflammatory signals induce feedback and feedforward systems that provide temporal control. Although glucocorticoids can repress inflammatory gene expression, glucocorticoid receptor recruitment increases expression of negative feedback and feedforward regulators, including the phosphatase, DUSP1, the ubiquitin-modifying enzyme, TNFAIP3, or the mRNAdestabilizing protein, ZFP36. Moreover, glucocorticoid receptor cooperativity with factors, including nuclear factor-B (NF-B), may enhance regulator expression to promote repression. Conversely, MAPKs, which are inhibited by glucocorticoids, provide feedforward control to limit expression of the transcription factor IRF1, and the chemokine, CXCL10. We propose that modulation of feedback and feedforward control can determine repression or resistance of inflammatory gene expression toglucocorticoid.

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Glucocorticoid and TNF signaling converge at A20 (TNFAIP3) to repress airway smooth muscle cytokine expression

Abstract: Sasse SK, Altonsy MO, Kadiyala V, Cao G, Panettieri RA Jr, Gerber AN. Glucocorticoid and TNF signaling converge at A20 (TNFAIP3) to repress airway smooth muscle cytokine expression. Am

Cited by 24 publications

References 69 publications

DUSP1 Maintains IRF1 and Leads to Increased Expression of IRF1-dependent Genes

DUSP1 Maintains IRF1 and Leads to Increased Expression of IRF1-dependent Genes

Modulation of allergic inflammation in the lung by a peptide derived from Mycobacteria tuberculosis chaperonin 60.1

Glucocorticoid and cytokine crosstalk: Feedback, feedforward, and co-regulatory interactions determine repression or resistance

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