Tristetraprolin and Its Role in Regulation of Airway Inflammation

Prabhala, Pavan; Ammit, Alaina J.

doi:10.1124/mol.114.095984

Cited by 25 publications

(31 citation statements)

References 144 publications

(178 reference statements)

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“…But this approach cannot give clear-cut answers, because as we have previously published (12), MKP-1 is in an inter-dependent ying-yang relationship with another anti-inflammatory protein -TTP (tristetraprolin). TTP is an anti-inflammatory protein that induces the decay of mRNAs encoding several cytokines, including those that drive COPD pathogenesis, including IL-8 (27).…”

Section: Discussionmentioning

confidence: 99%

Roflumilast N-Oxide in Combination with Formoterol Enhances the Antiinflammatory Effect of Dexamethasone in Airway Smooth Muscle Cells

Patel¹,

Rahman²,

Baehring

et al. 2017

Am J Respir Cell Mol Biol

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Roflumilast is an orally active phosphodiesterase 4 (PDE4) inhibitor approved for use in chronic obstructive pulmonary disease. Roflumilast N-oxide (RNO) is the active metabolite of roflumilast and has demonstrated anti-inflammatory impact in vivo and in vitro. To date, the effect of RNO on the synthetic function of airway smooth muscle (ASM) cells is unknown. We address this herein and investigate the effect of RNO on β2-adrenoceptor-mediated, cAMPdependent responses in ASM cells in vitro, and whether RNO enhances steroid-induced repression of inflammation. RNO (0.001-1000 nM) alone had no effect on AMP production from ASM cells, and significant potentiation of the long-acting β2-agonist formoterol-induced cAMP could only be achieved at the highest concentration of RNO tested (1000 nM). At this concentration, RNO exerted a small, but not significantly different, potentiation of formoterolinduced expression of anti-inflammatory mitogen-activated protein kinase phosphatase 1 (MKP-1). Consequently, tumor necrosis factor (TNF)-induced IL-8 secretion was unaffected by RNO in combination with formoterol. However, as there was the potential for PDE4 inhibitors and LABAs to interact with corticosteroids to achieve superior anti-inflammatory efficacy, we examined whether RNO, alone or in combination with formoterol, enhanced the antiinflammatory effect of dexamethasone by measuring the impact on IL-8 secretion. While RNO alone did not significantly enhance cytokine repression achieved with steroids; RNO in combination with formoterol significantly enhanced the anti-inflammatory effect of dexamethasone in ASM cells. This was linked to increased MKP-1 expression in ASM cells, suggesting a molecular mechanism responsible for augmented anti-inflammatory actions of combination therapeutic approaches that include RNO.

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Section: Discussionmentioning

confidence: 99%

Roflumilast N-Oxide in Combination with Formoterol Enhances the Antiinflammatory Effect of Dexamethasone in Airway Smooth Muscle Cells

Patel¹,

Rahman²,

Baehring

et al. 2017

Am J Respir Cell Mol Biol

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“…We suggest that a better approach is to gain an in depth understanding of the temporal regulation of TTP expression and control of its anti‐inflammatory activity by p38 MAPK. Understanding cytokine regulatory networks in this way will allow future development of novel pharmacotherapeutic approaches that repress pro‐inflammatory cytokines while ensuring that vital, anti‐inflammatory proteins necessary for disease resolution remain operational (reviewed in [Prabhala and Ammit, ]).…”

mentioning

confidence: 99%

Corticosteroid‐Induced MKP‐1 Represses Pro‐Inflammatory Cytokine Secretion by Enhancing Activity of Tristetraprolin (TTP) in ASM Cells

Prabhala

Bunge

et al. 2016

Journal Cellular Physiology

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Exaggerated cytokine secretion drives pathogenesis of a number of chronic inflammatory diseases, including asthma. Anti-inflammatory pharmacotherapies, including corticosteroids, are front-line therapies and although they have proven clinical utility, the molecular mechanisms responsible for their actions are not fully understood. The corticosteroid-inducible gene, mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1, DUSP1) has emerged as a key molecule responsible for the repressive effects of steroids. MKP-1 is known to deactivate p38 MAPK phosphorylation and can control the expression and activity of the mRNA destabilizing protein-tristetraprolin (TTP). But whether corticosteroid-induced MKP-1 acts via p38 MAPK-mediated modulation of TTP function in a pivotal airway cell type, airway smooth muscle (ASM), was unknown. While pretreatment of ASM cells with the corticosteroid dexamethasone (preventative protocol) is known to reduce ASM synthetic function in vitro, the impact of adding dexamethasone after stimulation (therapeutic protocol) had not been explored. Whether dexamethasone modulates TTP in a p38 MAPK-dependent manner in this cell type was also unknown. We address this herein and utilize an in vitro model of asthmatic inflammation where ASM cells were stimulated with the pro-asthmatic cytokine tumor necrosis factor (TNF) and the impact of adding dexamethasone 1 h after stimulation assessed. IL-6 mRNA expression and protein secretion was significantly repressed by dexamethasone acting in a temporally distinct manner to increase MKP-1, deactivate p38 MAPK, and modulate TTP phosphorylation status. In this way, dexamethasone-induced MKP-1 acts via p38 MAPK to switch on the mRNA destabilizing function of TTP to repress pro-inflammatory cytokine secretion from ASM cells. J. Cell. Physiol. 231: 2153-2158, 2016. © 2016 Wiley Periodicals, Inc.

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“…TTP is an immediate early response gene that functions to destabilize mRNA of many cytokines (5), including those involved in asthma (26). TTP confers this mRNA instability and degradation by binding the conserved adenosine/uridinerich element present within the 3=-untranslated region of many mRNA transcripts (6,15).…”

mentioning

confidence: 99%

Temporal regulation of cytokine mRNA expression by tristetraprolin: dynamic control by p38 MAPK and MKP-1

Prabhala

Bunge

Rahman

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Prabhala P, Bunge K, Rahman MM, Ge Q, Clark AR, Ammit AJ. Temporal regulation of cytokine mRNA expression by tristetraprolin: dynamic control by p38 MAPK and MKP-1. Am J Physiol Lung Cell Mol Physiol 308: L973-L980, 2015. First published February 27, 2015 doi:10.1152/ajplung.00219.2014.-Cytokines drive many inflammatory diseases, including asthma. Understanding the molecular mechanisms responsible for cytokine secretion will allow us to develop novel strategies to repress inflammation in the future. Harnessing the power of endogenous anti-inflammatory proteins is one such strategy. In this study, we investigate the p38 MAPKmediated regulatory interaction of two anti-inflammatory proteins, mitogen-activated protein kinase phosphatase 1 (MKP-1) and tristetraprolin (TTP), in the context of asthmatic inflammation. Using primary cultures of airway smooth muscle cells in vitro, we explored the temporal regulation of IL-6 cytokine mRNA expression upon stimulation with TNF-␣. Intriguingly, the temporal profile of mRNA expression was biphasic. This was not due to COX-2-derived prostanoid upregulation, increased expression of NLRP3 inflammasome components, or upregulation of the cognate receptor for TNF-␣-TNFR1. Rather, the biphasic nature of TNF-␣-induced IL-6 mRNA expression was regulated temporally by the RNA-destabilizing molecule, TTP. Importantly, TTP function is controlled by p38 MAPK, and our study reveals that its expression in airway smooth muscle cells is p38 MAPK-dependent and its anti-inflammatory activity is also controlled by p38 MAPK-mediated phosphorylation. MKP-1 is a MAPK deactivator; thus, by controlling p38 MAPK phosphorylation status in a temporally distinct manner, MKP-1 ensures that TTP is expressed and made functional at precisely the correct time to repress cytokine expression. Together, p38 MAPK, MKP-1, and TTP may form a regulatory network that exerts significant control on cytokine secretion in proasthmatic inflammation through precise temporal signaling. p38 MAPK; tristetraprolin; MKP-1; inflammation; IL-6 MANY CHRONIC INFLAMMATORY diseases are a common consequence of overactive inflammatory signaling pathways. Hence, using these pathways as potential drug targets represents a way to re-establish control and attenuate the severity of such chronic inflammatory diseases. Asthma is a chronic inflammatory disease, which is characterized by reversible airway obstruction, structural remodeling, and airway hyperresponsiveness. A plethora of proinflammatory cytokines have been implicated in the pathophysiology of asthma. The common therapies for asthma include glucocorticoids and ␤ 2 -agonists; however, there is still a proportion of the population for which this treatment is ineffective. Hence, a need has arisen to find alternative anti-inflammatory strategies, such as using smallmolecule inhibitors of inflammatory cascades or using agents that could increase activity of anti-inflammatory proteins. To achieve this goal, a greater understanding of the regulatory networks that control cytokines are u...

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Tristetraprolin and Its Role in Regulation of Airway Inflammation

Cited by 25 publications

References 144 publications

Roflumilast N-Oxide in Combination with Formoterol Enhances the Antiinflammatory Effect of Dexamethasone in Airway Smooth Muscle Cells

Roflumilast N-Oxide in Combination with Formoterol Enhances the Antiinflammatory Effect of Dexamethasone in Airway Smooth Muscle Cells

Corticosteroid‐Induced MKP‐1 Represses Pro‐Inflammatory Cytokine Secretion by Enhancing Activity of Tristetraprolin (TTP) in ASM Cells

Temporal regulation of cytokine mRNA expression by tristetraprolin: dynamic control by p38 MAPK and MKP-1

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