Rahman Md Mostafizur, Rumzhum Nowshin N, Morris Jonathan C, Clark Andrew R, Verrills Nicole M, Ammit Alaina J
Faculty of Pharmacy University of Sydney. NSW 2006 Australia.
School of Chemistry University of NSW. NSW 2052 Australia.
Sci Rep. 2015 May 18;5:10063. doi: 10.1038/srep10063.
PP2A is a master controller of multiple inflammatory signaling pathways. It is a target in asthma; however the molecular mechanisms by which PP2A controls inflammation warrant further investigation. In A549 lung epithelial cells in vitro we show that inhibition of basal PP2A activity by okadaic acid (OA) releases restraint on MAPKs and thereby increases MAPK-mediated pro-asthmatic cytokines, including IL-6 and IL-8. Notably, PP2A inhibition also impacts on the anti-inflammatory protein - tristetraprolin (TTP), a destabilizing RNA binding protein regulated at multiple levels by p38 MAPK. Although PP2A inhibition increases TTP mRNA expression, resultant TTP protein builds up in the hyperphosphorylated inactive form. Thus, when PP2A activity is repressed, pro-inflammatory cytokines increase and anti-inflammatory proteins are rendered inactive. Importantly, these effects can be reversed by the PP2A activators FTY720 and AAL(s), or more specifically by overexpression of the PP2A catalytic subunit (PP2A-C). Moreover, PP2A plays an important role in cytokine expression in cells stimulated with TNFα; as inhibition of PP2A with OA or PP2A-C siRNA results in significant increases in cytokine production. Collectively, these data reveal the molecular mechanisms of PP2A regulation and highlight the potential of boosting the power of endogenous phosphatases as novel anti-inflammatory strategies to combat asthmatic inflammation.
PP2A是多种炎症信号通路的主控制器。它是哮喘的一个靶点；然而，PP2A控制炎症的分子机制值得进一步研究。在体外培养的A549肺上皮细胞中，我们发现用冈田酸（OA）抑制基础PP2A活性可解除对丝裂原活化蛋白激酶（MAPKs）的抑制，从而增加MAPK介导的促哮喘细胞因子，包括白细胞介素-6（IL-6）和白细胞介素-8（IL-8）。值得注意的是，PP2A抑制还会影响抗炎蛋白——锌指蛋白36（TTP），这是一种由p38 MAPK在多个水平调控的不稳定RNA结合蛋白。虽然PP2A抑制会增加TTP mRNA表达，但产生的TTP蛋白会以高度磷酸化的无活性形式积累。因此，当PP2A活性受到抑制时，促炎细胞因子增加，抗炎蛋白失活。重要的是，这些作用可以被PP2A激活剂FTY720和AAL（s）逆转，或者更具体地说，可以通过过表达PP2A催化亚基（PP2A-C）来逆转。此外，PP2A在用肿瘤坏死因子α（TNFα）刺激的细胞中细胞因子表达中起重要作用；因为用OA或PP2A-C小干扰RNA（siRNA）抑制PP2A会导致细胞因子产生显著增加。总的来说，这些数据揭示了PP2A调控的分子机制，并突出了增强内源性磷酸酶的作用作为对抗哮喘炎症的新型抗炎策略的潜力。
