Interleukin‐1α and tumour necrosis factor‐α modulate airway smooth muscle DNA synthesis by induction of cyclo‐oxygenase‐2: inhibition by dexamethasone and fluticasone propionate

Vlahos, Ross; Stewart, Alastair G.

doi:10.1038/sj.bjp.0702424

Cited by 49 publications

(28 citation statements)

References 50 publications

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“…Airway smooth muscle (ASM) has now been recognized as a novel player in the pathogenesis of asthma (3,4) and might therefore be expected to be a prominent therapeutic target for inhaled steroids (5). In line with this, we and others showed that GCs were effective in abrogating the expression of a number of pro-inflammatory mediators including cytokines, chemokines, and adhesion molecules in ASM cells (5)(6)(7)(8)(9)(10).…”

supporting

confidence: 53%

Cytokines Induce an Early Steroid Resistance in Airway Smooth Muscle Cells

Tliba¹,

Damera²,

Banerjee³

et al. 2008

Am J Respir Cell Mol Biol

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We have previously shown that long-term treatment of airway smooth muscle (ASM) cells with a combination of TNF-a and IFN-g impaired steroid anti-inflammatory action through the up-regulation of glucocorticoid receptor beta isoform (GRb) (Mol Pharmacol 2006;69:588-596). We here found that steroid actions could also be suppressed by short-term exposure of ASM cells to TNF-a and IFN-g (6 h) as shown by the abrogated glucocorticoid responsive element (GRE)-dependent gene transcription; surprisingly, neither GRa nuclear translocation nor GRb expression was affected by cytokine mixture. The earlier induction of CD38, a molecule recently involved in asthma, seen with TNF-a and IFN-g combination but not with cytokine alone, was also completely insensitive to steroid pretreatment. Chromatin-immunoprecipitation (IP) and siRNA strategies revealed not only increased binding of interferon regulatory factor 1 (IRF-1) transcription factor to CD38 promoter, but also its implication in regulating CD38 gene transcription. Interestingly, the capacity of fluticasone to completely inhibit TNF-a-induced IRF-1 expression, IRF-1 DNA binding, and transactivation activities was completely lost in cells exposed to TNF-a and IFN-g in combination. This early steroid dysfunction seen with cytokine combination could be reproduced by enhancing IRF-1 cellular levels using constitutively active IRF-1, which dose-dependently inhibited GRE-dependent gene transcription. Consistently, reducing IRF-1 cellular levels using siRNA approach significantly restored steroid transactivation activities. Collectively, our findings demonstrate for the first time that IRF-1 is a novel alternative GRb-independent mechanism mediating steroid dysfunction induced by pro-asthmatic cytokines, in part via the suppression of GRa activities.

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supporting

confidence: 53%

Cytokines Induce an Early Steroid Resistance in Airway Smooth Muscle Cells

Tliba¹,

Damera²,

Banerjee³

et al. 2008

Am J Respir Cell Mol Biol

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“…Multiple cytokines have been demonstrated to alter COX-2 expression in vitro. Proinflammatory cytokines including TNF-␣ (13,14), IL-1␣ (14,15), and IFN-␥ (16,17) have been demonstrated to induce COX-2 expression, whereas antiinflammatory cytokines such as IL-4 (18), IL-13 (19,20), and IL-10 (21) can inhibit COX-2 induction. The pleiotropic cytokine TGF-␤ can enhance (22) or inhibit (23) COX-2 expression, depending upon the cell type tested.…”

Section: Il-10 Is a Central Regulator Of Cyclooxygenase-2 Expression mentioning

confidence: 99%

“…For the HPLC assay of eicosanoids, spleen cell cultures were incubated for 30 min at 37°C with up to 7.5 M [5,6,8,9,11,12,14, H]arachidonic acid (AA) (155 Ci/mmol; New England Nuclear, Boston, MA) in serumfree medium. After incubation, the medium was collected and centrifuged to remove cellular debris.…”

Section: Hplcmentioning

confidence: 99%

IL-10 Is a Central Regulator of Cyclooxygenase-2 Expression and Prostaglandin Production

Berg

Zhang

Lauricella

et al. 2001

The Journal of Immunology

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IL-10 is a potent anti-inflammatory and immune regulatory cytokine. IL-10−/− mice produce exaggerated amounts of inflammatory cytokines when stimulated with LPS, indicating that endogenous IL-10 is a central regulator of inflammatory cytokine production in vivo. PGs are lipid mediators that are also produced in large amounts during the inflammatory response. To study the role of IL-10 in the regulation of PG production during the acute inflammatory response, we evaluated LPS-induced cyclooxygenase (COX) expression and PG production in wild-type (wt) and IL-10−/− mice. LPS-induced PGE2 production from IL-10−/− spleen cells was 5.6-fold greater than that from wt spleen cells. LPS stimulation resulted in the induction of COX-2 mRNA and protein in both wt and IL-10−/− spleen cells; however, the magnitude of increase in COX-2 mRNA was 5.5-fold greater in IL-10−/− mice as compared with wt mice. COX-1 protein levels were not affected by LPS stimulation in either wt or IL-10−/− mice. Neutralization of IFN-γ, TNF-α, or IL-12 markedly decreased the induction of COX-2 in IL-10−/− spleen cells, suggesting that increased inflammatory cytokine production mediates much of the COX-2 induction in IL-10−/− mice. Treatment of IL-10−/− mice with low doses of LPS resulted in a marked induction of COX-2 mRNA in the spleen, whereas wt mice had minimal expression of COX-2 mRNA. These findings indicate that, in addition to IL-10’s central role in the regulation of inflammatory cytokines, endogenous IL-10 is an important regulator of PG production in the response to LPS.

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“…First, the effects of GC seem to be highly gene-specific. For example, reports showed that dexamethasone can effectively inhibit cytokine-induced IL-6, RANTES (Ammit et al, 2002), eotaxin (Pang and Knox, 2001), or cyclooxygenase-2 expression (Vlahos and Stewart, 1999), whereas it has no effect on cytokine-induced ICAM-1 expression (Amrani et al, 1999). Second, GC suppressive effect seems to be time-dependent, because dexamethasone partially abrogates cytokine-mediated ICAM-1 expression at early time points but has no effect at later time points (Amrani et al, 1999).…”

mentioning

confidence: 99%

CD38 Expression Is Insensitive to Steroid Action in Cells Treated with Tumor Necrosis Factor-α and Interferon-γ by a Mechanism Involving the Up-Regulation of the Glucocorticoid Receptor β Isoform

Tliba

Cidlowski²,

Amrani³

2005

Mol Pharmacol

100

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Evidence shows that the CD38 molecule, recently involved in the two main features of asthma, bronchial hyper-responsiveness and airway inflammation, could represent a new potential therapeutic target for asthma. In this study, we investigated whether glucocorticoid (GC), the most effective treatment for lung diseases, can affect CD38 expression in human airway smooth muscle (ASM) cells treated with different pro-inflammatory cytokines, such as tumor necrosis factor-␣ (TNF␣) and interferons (IFNs). We found that CD38 expression induced by TNF␣ alone was completely abrogated by fluticasone (100 nM), dexamethasone (1 M), or budesonide (100 nM). In contrast, the synergistic induction of CD38 by the combination of TNF␣ with IFN␥ or IFN␤, but not with IL-1␤ or IL-13, was completely insensitive to the GC inhibitory effects. We also found that TNF␣ and IFN␥ impaired GC responsiveness by inhibiting steroid induced both 1) GR␣-DNA binding activity and 2) GCresponsive element-(GRE)-dependent gene transcription. Although levels of the GC receptor (GR) ␣ isoform remained unchanged, expression of GR␤, the dominant-negative GR isoform, was synergistically increased by TNF␣ and IFN␥ with a GR␣/GR␤ ratio of 1 to 3. More importantly, fluticasone failed to induce GRE-dependent gene transcription and to suppress TNF␣-induced CD38 expression in ASM cells transfected with constitutively active GR␤. We conclude that, upon pro-inflammatory cytokine stimulation, CD38 expression becomes insensitive to GC action by a mechanism involving the up-regulation of GR␤ isoform, thus providing a novel in vitro cellular model to dissect GC resistance in primary cells.

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Interleukin‐1α and tumour necrosis factor‐α modulate airway smooth muscle DNA synthesis by induction of cyclo‐oxygenase‐2: inhibition by dexamethasone and fluticasone propionate

Cited by 49 publications

References 50 publications

Cytokines Induce an Early Steroid Resistance in Airway Smooth Muscle Cells

Cytokines Induce an Early Steroid Resistance in Airway Smooth Muscle Cells

IL-10 Is a Central Regulator of Cyclooxygenase-2 Expression and Prostaglandin Production

CD38 Expression Is Insensitive to Steroid Action in Cells Treated with Tumor Necrosis Factor-α and Interferon-γ by a Mechanism Involving the Up-Regulation of the Glucocorticoid Receptor β Isoform

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