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

Md Mostafizur Rahman1, Nowshin N Rumzhum1, Philip M Hansbro2

  • 1Faculty of Pharmacy, University of Sydney, NSW 2006, Australia.

Cellular Signalling
|January 29, 2016
PubMed

Insights

Novel compounds activate protein phosphatase 2A (PP2A) to boost the anti-inflammatory function of tristetraprolin (TTP), offering new therapeutic strategies for chronic respiratory diseases.

Area of Science:

  • Immunology
  • Molecular Biology
  • Pharmacology

Background:

  • Chronic respiratory diseases involve inflammation, with some conditions like severe asthma and COPD resisting standard anti-inflammatory treatments.
  • Tristetraprolin (TTP) is an anti-inflammatory protein that promotes mRNA decay of pro-inflammatory cytokines, crucial in respiratory disorders.
  • TTP activity is regulated by phosphorylation, with protein phosphatase 2A (PP2A) dephosphorylating and activating TTP.

Purpose of the Study:

  • To investigate if PP2A activators, FTY720 and AAL(S), can suppress cytokine production in a cellular model of airway inflammation.
  • To explore the role of PP2A activation in regulating TTP's anti-inflammatory function in the context of respiratory diseases.

Main Methods:

  • Utilized A549 lung epithelial cells stimulated with tumor necrosis factor α (TNFα) in vitro.
  • Assessed PP2A activity, mRNA expression, and protein secretion of interleukin 8 (IL-8) and IL-6.
  • Employed small interfering RNA (siRNA) to specifically knockdown TTP expression.

Main Results:

  • PP2A activators significantly increased PP2A activity and inhibited TNFα-induced IL-8 and IL-6 mRNA and protein.
  • The suppressive effect of PP2A activators was independent of TTP mRNA expression levels.
  • Specific TTP knockdown reversed the inhibitory effects of FTY720 on IL-8 and IL-6 production, confirming TTP's role.

Conclusions:

  • PP2A activators enhance TTP's anti-inflammatory function by shifting the TTP phosphorylation balance towards the active, unphosphorylated form.
  • These findings suggest PP2A activators are promising pharmacotherapeutic agents for managing inflammation in respiratory diseases.
  • The study highlights a novel mechanism for controlling cytokine production relevant to treating severe asthma and COPD.
Keywords:
AsthmaInflammationProtein phosphatase 2ATNFαTristetraprolin

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