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

作者：Rahman Md Mostafizur; Rumzhum Nowshin N; Han**ro Philip M; Morris Jonathan C; Clark Andrew R; Verrills Nicole M; Ammit Alaina J^*

来源：Cellular Signalling, 2016, 28(4): 325-334.

DOI：10.1016/j.cellsig.2016.01.009

• Protein phosphatase 2A
• Tristetraprolin
• TNF alpha
• Inflammation
• Asthma

Chronic respiratory diseases are driven by inflammation, but some clinical conditions (severe asthma, COPD) are refractory to conventional anti-inflammatory therapies. Thus, novel anti-inflammatory strategies are necessary. The mRNA destabilizing protein, tristetraprolin (TTP), is an anti-inflammatory molecule that functions to induce mRNA decay of cytoldnes that drive pathogenesis of respiratory disorders. TTP is regulated by phosphorylation and protein phosphatase 2A (PP2A) is responsible for dephosphorylating (and hence activating) TIP, amongst other targets. PP2A is activated by small molecules, FTY720 and AAL(S), and in this study we examine whether these compounds repress cytolcine production in a cellular model of airway inflammation using A549 lung epithelial cells stimulated with tumor necrosis factor alpha (TNF alpha) in vitro. PP2A activators significantly increase TNF alpha-induced PP2A activity and inhibit mRNA expression and protein secretion of interleukin 8 (IL-8) and IL-6; two key pro-inflammatory cytokines implicated in respiratory disease and TIP targets. The effect of PP2A activators is not via an increase in TNF alpha-induced TTP mRNA expression; instead we demonstrate a link between PP2A activation and TTP anti-inflammatory function by showing that specific knockdown of TTP with siRNA reversed the repression of TNF alpha-induced IL-8 and IL-6 mRNA expression and protein secretion by FIY720. Therefore we propose that PP2A activators affect the dynamic equilibrium regulating TTP; shifting the equilibrium from phosphorylated (inactive) towards unphosphorylated (active) but unstable TTP. PP2A activators boost the anti-inflammatory function of TIP and have implications for future pharmacotherapeutic strategies to combat inflammation in respiratory disease.

• 出版日期2016-4