TNF<i>α</i> reduces tachykinin, PGE<sub>2</sub>‐dependent, relaxation of the cultured mouse trachea by increasing the activity of COX‐2

Bachar, Ofir; Rose, Andrew C; Adner, Mikael; Wang, Xudong; Prendergast, Clodagh; Kempf, Ashley; Shankley, Nigel P.; Cardell, Lars-Olaf

doi:10.1038/sj.bjp.0706067

Cited by 17 publications

(13 citation statements)

References 37 publications

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“…A direct action of TNFα on ASM function as a plausible mechanism for the enhanced airway responsiveness is evidenced by previous reports showing (i) enhanced ex vivo contractility to different contractile agonists (Adner et al, 2002;Sakai et al, 2004a, b;Chen et al, 2003) or (ii) impaired responses to β2-adrenoceptor agonists (Chen et al, 2003;Bachar et al, 2005;Wills-Karp et al, 1993) following TNFα treatment. The mechanisms by which TNFα promotes these "pro-asthmatic" responses are still unknown.…”

Section: Discussionmentioning

confidence: 80%

Essential role of IFNβ and CD38 in TNFα-induced airway smooth muscle hyper-responsiveness

et al. 2008

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We recently identified autocrine interferon (IFN)β as a novel mechanism mediating tumor necrosis factor (TNF)α-induced expression of inflammatory genes in airway smooth muscle (ASM) cells, including CD38, known to regulate calcium signaling. Here, we investigated the putative involvement of IFNβ in regulating TNFα-induced airway hyper-responsiveness (AHR), a defining feature of asthma. Using our pharmacodynamic model to assess ex vivo AHR isolated murine tracheal rings, we found that TNFα-induced enhanced contractile responses to carbachol and bradykinin was abrogated by neutralizing anti-IFNβ antibody or in tracheal rings deficient in CD38. In cultured human ASM cells, where CD38 has been involved in TNFα-induced enhanced calcium signals to carbachol and bradykinin, we found that neutralizing anti-IFNβ prevented TNFα enhancing action only on carbachol responses but not to that induced by bradykinin. In a well-characterized model of allergic asthma (mice sensitized and challenged with Aspergillus fumigatus (Af)), we found heightened expression of both IFNβ and CD38 in the airways. Furthermore, allergen-associated AHR to methacholine, assessed by lung resistance and dynamic compliance, was completely suppressed in CD38-deficient mice, despite the preservation of airway inflammation. These data provide the first evidence that ASM-derived IFNβ and CD38 may play a significant role in the development of TNFα-associated AHR.

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Section: Discussionmentioning

confidence: 80%

Essential role of IFNβ and CD38 in TNFα-induced airway smooth muscle hyper-responsiveness

et al. 2008

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“…One is IL-1␤-induced increase of expression and activity of G-protein-coupled receptor kinase 2 leading to desensitization of ␤ 2 AR, as demonstrated in vivo in rat lung after intratracheal instillation of IL-1␤, where dexamethasone completely prevented the increased expression of G-protein-coupled receptor kinase 2 and G-protein-coupled receptor kinase activity by IL-1␤ (Mak et al, 2002). Another mechanism is heterologous desensitization of ␤ 2 AR through the induction of COX-2 by the cytokines, subsequent release of prostaglandin E 2 , and activation of protein kinase A via prostaglandin EP 2 receptors, leading to uncoupling of ␤ 2 AR from stimulatory G-protein (Gs), as shown in mouse trachea (Bachar et al, 2005) and in human airway smooth muscle cells (Shore et al, 1997). GCs are known inhibitors of the COX-2 induction, and thus have ability to prevent this process.…”

Section: Discussionmentioning

confidence: 99%

“…The other prong was connected to a displacement device, allowing adjustment of the distance between the two parallel prongs. To avoid any effect of prostanoid secretion in the preparations (Bachar et al, 2005), indomethacin was always present 30 min before and during agonist administration.…”

Section: Methodsmentioning

confidence: 99%

Budesonide Prevents Cytokine-Induced Decrease of the Relaxant Responses to Formoterol and Terbutaline, but Not to Salmeterol, in Mouse Trachea

Adner

Larsson

Säfholm

et al. 2010

The Journal of Pharmacology and Experimental Therapeutics

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During asthma exacerbations, increased airway inflammation may impair the effects of ␤ 2 -adrenoceptor (␤ 2 AR) agonists. It is unclear whether this impairment is prevented by inhaled glucocorticoids (GCs). We have investigated the relaxation of carbachol-contracted mouse tracheal segments to the ␤ 2 AR agonists formoterol, terbutaline, and salmeterol. The segments were pre-exposed for 4 days to the proinflammatory cytokines tumor necrosis factor ␣ (100 ng/ml) and interleukin-1␤ (10 ng/ml) with or without the GC, budesonide (1 M). Formoterol and terbutaline induced greater maximal relaxation (R max ) than salmeterol. The cytokines decreased R max of all ␤ 2 AR agonists, whereas budesonide had no effect. However, after concomitant treatment with cytokines and budesonide, the R max values of formoterol and terbutaline were not impaired, whereas budesonide did not prevent the decrease in the R max of salmeterol. A similar pattern was observed for cAMP production by the agonists. In tracheal smooth muscle, ␤ 2 AR mRNA was not affected by the cytokines but increased with budesonide. However, the cytokines markedly increased cyclooxygenase (COX)-2 mRNA expression, which may lead to heterologous desensitization of ␤ 2 AR. It is noteworthy that the cytokine-induced increase of COX-2 was blocked by concomitant budesonide suggesting that heterologous desensitization of ␤ 2 AR by the cytokines may be prevented by budesonide treatment. Budesonide prevented cytokine-induced impairment of the tracheal relaxation and ␤ 2 AR/cAMP signaling for formoterol but not for salmeterol. This suggests that differences exist between formoterol and salmeterol in ␤ 2 AR coupling/activation and/or signal transduction upstream of cAMP. These results imply that maximal bronchodilator effects of formoterol, but not of salmeterol, are maintained by budesonide treatment during periods with increased inflammation, such as asthma exacerbations.

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“…iScript reverse transcriptase (Bio-Rad, Hercules, CA) was used to synthesize cDNA, which was subjected to quantitative real-time PCR analysis using SYBR Green reaction mix (Sigma-Aldrich) and an iCycler with IQ5 software (Bio-Rad). Relative input mRNA levels were determined using the cycle threshold (2 Ϫ⌬⌬CT ) method, with 18S as the reference, using previously characterized primers (4).…”

Section: Methodsmentioning

confidence: 99%

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

Hobbs¹,

Goettel

Liang³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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TNF and epidermal growth factor (EGF) are well-known stimuli of cyclooxygenase (COX)-2 expression, and TNF stimulates transactivation of EGF receptor (EGFR) signaling to promote survival in colon epithelial cells. We hypothesized that COX-2 induction and cell survival signaling downstream of TNF are mediated by EGFR transactivation. TNF treatment was more cytotoxic to COX-2−/−mouse colon epithelial (MCE) cells than wild-type (WT) young adult mouse colon (YAMC) epithelial cells or COX-1−/−cells. TNF also induced COX-2 protein and mRNA expression in YAMC cells, but blockade of EGFR kinase activity or expression inhibited COX-2 upregulation. TNF-induced COX-2 expression was reduced and absent in EGFR−/−and TNF receptor-1 (TNFR1) knockout MCE cells, respectively, but was restored upon expression of the WT receptors. Inhibition of mediators of EGFR transactivation, Src family kinases and p38 MAPK, blocked TNF-induced COX-2 protein and mRNA expression. Finally, TNF injection increased COX-2 expression in colon epithelium of WT, but not kinase-defective EGFRwa2and EGFRwa5, mice. These data indicate that TNFR1-dependent transactivation of EGFR through a p38- and/or an Src-dependent mechanism stimulates COX-2 expression to promote cell survival. This highlights an EGFR-dependent cell signaling pathway and response that may be significant in colitis-associated carcinoma.

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TNFα reduces tachykinin, PGE₂‐dependent, relaxation of the cultured mouse trachea by increasing the activity of COX‐2

Cited by 17 publications

References 37 publications

Essential role of IFNβ and CD38 in TNFα-induced airway smooth muscle hyper-responsiveness

Essential role of IFNβ and CD38 in TNFα-induced airway smooth muscle hyper-responsiveness

Budesonide Prevents Cytokine-Induced Decrease of the Relaxant Responses to Formoterol and Terbutaline, but Not to Salmeterol, in Mouse Trachea

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

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TNFα reduces tachykinin, PGE2‐dependent, relaxation of the cultured mouse trachea by increasing the activity of COX‐2

Cited by 17 publications

References 37 publications

Essential role of IFNβ and CD38 in TNFα-induced airway smooth muscle hyper-responsiveness

Essential role of IFNβ and CD38 in TNFα-induced airway smooth muscle hyper-responsiveness

Budesonide Prevents Cytokine-Induced Decrease of the Relaxant Responses to Formoterol and Terbutaline, but Not to Salmeterol, in Mouse Trachea

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

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TNFα reduces tachykinin, PGE₂‐dependent, relaxation of the cultured mouse trachea by increasing the activity of COX‐2