Activating protein phosphatase 2A (PP2A) enhances tristetraprolin (TTP) anti-inflammatory function in A549 lung epithelial cells

Rahman, Md. Mostafizur; Rumzhum, Nowshin N.; Hansbro, Philip M.; Morris, Jonathan C.; Clark, Andrew R.; Verrills, Nicole M.; Ammit, Alaina J.

doi:10.1016/j.cellsig.2016.01.009

Cited by 40 publications

(53 citation statements)

References 33 publications

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“…Our recent studies have underscored the anti-inflammatory impact of PP2A activation on respiratory inflammation in vitro 4512. Both well-known (FTY72045): and more recently-reported (AAL(S)45; theophylline12) molecules that increase PP2A enzymatic activity can significantly repress cytokine production in vitro .…”

Section: Resultsmentioning

confidence: 77%

“…The classical PP2A activator is FTY720 and we have previously published that FTY720 significantly increases TNF-induced PP2A activity in A549 cells5. In the current study we were interested in examining the impact of the phosphorylated form of FTY720, i.e.…”

Section: Resultsmentioning

confidence: 99%

“…PP2A levels (and therefore activity) were reduced in these models of asthma2 and PP2A activity could be reinstated pharmacologically to repress hallmark features of allergic and rhinovirus-induced airway disease23. In vitro , we have shown that PP2A activators inhibit cytokine production in a cellular model of airway inflammation using A549 lung epithelial cells stimulated with tumor necrosis factor (TNF) in vitro 45.…”

mentioning

confidence: 99%

“…PP2A-activating drugs (now collectively referred to as PADs) have emerged as novel therapeutics in cancer6 and offer demonstrable potential as novel anti-inflammatories in chronic respiratory disease2345. The best known PAD is the sphingosine analog FTY720 (Fingolimod).…”

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confidence: 99%

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The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells

Rahman

Prünte

Lebender

et al. 2016

Sci Rep

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Protein phosphatase 2A (PP2A) activity can be enhanced pharmacologically by PP2A-activating drugs (PADs). The sphingosine analog FTY720 is the best known PAD and we have shown that FTY720 represses production of pro-inflammatory cytokines responsible for respiratory disease pathogenesis. Whether its phosphorylated form, FTY720-P, also enhances PP2A activity independently of the sphingosine 1-phosphate (S1P) pathway was unknown. Herein, we show that FTY720-P enhances TNF-induced PP2A phosphatase activity and significantly represses TNF-induced interleukin 6 (IL-6) and IL-8 mRNA expression and protein secretion from A549 lung epithelial cells. Comparing FTY720 and FTY720-P with S1P, we show that unlike S1P, the sphingosine analogs do not induce cytokine production on their own. In fact, FTY720 and FTY720-P significantly repress S1P-induced IL-6 and IL-8 production. We then examined their impact on expression of cyclooxygenase 2 (COX-2) and resultant prostaglandin E2 (PGE2) production. S1P did not increase production of this pro-inflammatory enzyme because COX-2 mRNA gene expression is NF-κB-dependent, and unlike TNF, S1P did not activate NF-κB. However, TNF-induced COX-2 mRNA expression and PGE2 secretion is repressed by FTY720 and FTY720-P. Hence, FTY720-P enhances PP2A activity and that PADs can repress production of pro-inflammatory cytokines and enzymes in A549 lung epithelial cells in a manner devoid of S1P agonism.

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Section: Resultsmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells

Rahman

Prünte

Lebender

et al. 2016

Sci Rep

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“…Several compounds have been shown to promote PP2A function, usually by disrupting interactions between the phosphatase and its inhibitory protein partners [108,109]. One such compound, a sphingolipid known as AAL(s), exerted TTP-dependent anti-inflammatory effects in an airway epithelial cell line [114,115]. AAL(s) and another PP2A agonist, the apolipoprotein E-derived peptide COG1410, exerted protective effects and prevented bone erosion in an experimental model of RA [9a].…”

Section: Therapeutic Implications Of the Regulation Of Ttp By Pp2a Anmentioning

confidence: 99%

The control of inflammation via the phosphorylation and dephosphorylation of tristetraprolin: a tale of two phosphatases

Clark

Dean

2016

Biochemical Society Transactions

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Twenty years ago, the first description of a tristetraprolin (TTP) knockout mouse highlighted the fundamental role of TTP in the restraint of inflammation. Since then, work from several groups has generated a detailed picture of the expression and function of TTP. It is a sequence-specific RNA-binding protein that orchestrates the deadenylation and degradation of several mRNAs encoding inflammatory mediators. It is very extensively post-translationally modified, with more than 30 phosphorylations that are supported by at least two independent lines of evidence. The phosphorylation of two particular residues, serines 52 and 178 of mouse TTP (serines 60 and 186 of the human orthologue), has profound effects on the expression, function and localisation of TTP. Here, we discuss the control of TTP biology via its phosphorylation and dephosphorylation, with a particular focus on recent advances and on questions that remain unanswered.

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Enhancing tristetraprolin activity reduces the severity of cigarette smoke‐induced experimental chronic obstructive pulmonary disease

et al. 2019

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Objective. Chronic obstructive pulmonary disease (COPD) is a progressive disease that causes significant mortality and morbidity worldwide and is primarily caused by the inhalation of cigarette smoke (CS). Lack of effective treatments for COPD means there is an urgent need to identify new therapeutic strategies for the underlying mechanisms of pathogenesis. Tristetraprolin (TTP) encoded by the Zfp36 gene is an anti-inflammatory protein that induces mRNA decay, especially of transcripts encoding inflammatory cytokines, including those implicated in COPD.Methods. Here, we identify a novel protective role for TTP in CSinduced experimental COPD using Zfp36 aa/aa mice, a genetically modified mouse strain in which endogenous TTP cannot be phosphorylated, rendering it constitutively active as an mRNAdestabilising factor. TTP wild-type (Zfp36 +/+ ) and Zfp36 aa/aa active C57BL/6J mice were exposed to CS for four days or eight weeks, and the impact on acute inflammatory responses or chronic features of COPD, respectively, was assessed. Results. After four days of CS exposure, Zfp36 aa/aa mice had reduced numbers of airway neutrophils and lymphocytes and mRNA expression levels of cytokines compared to wild-type controls. After eight weeks, Zfp36 aa/aa mice had reduced pulmonary inflammation, airway remodelling and emphysema-like alveolar enlargement, and lung function was improved. We then used pharmacological treatments in vivo (protein phosphatase 2A activator, AAL (S) , and the proteasome inhibitor, bortezomib) to promote the activation and stabilisation of TTP and show that hallmark features of CS-induced experimental COPD were ameliorated. Conclusion. Collectively, our ª

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Activating protein phosphatase 2A (PP2A) enhances tristetraprolin (TTP) anti-inflammatory function in A549 lung epithelial cells

Cited by 40 publications

References 33 publications

The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells

The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells

The control of inflammation via the phosphorylation and dephosphorylation of tristetraprolin: a tale of two phosphatases

Enhancing tristetraprolin activity reduces the severity of cigarette smoke‐induced experimental chronic obstructive pulmonary disease

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