title: Basal protein phosphatase 2A activity restrains cytokine expression: role for MAPKs and tristetraprolin.
abstract: 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.
authors.affiliation: Faculty of Pharmacy University of Sydney. NSW 2006 Australia.
authors.forename: Md Mostafizur
authors.initials: MM
authors.lastname: Rahman
authors.affiliation: Faculty of Pharmacy University of Sydney. NSW 2006 Australia.
authors.forename: Nowshin N
authors.initials: NN
authors.lastname: Rumzhum
authors.affiliation: School of Chemistry University of NSW. NSW 2052 Australia.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: Centre for Translational Inflammation Research School of Immunity and Infection University of Birmingham. Edgbaston B15 2TT United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Clark
authors.affiliation: School of Biomedical Sciences and Pharmacy Faculty of Health University of Newcastle. NSW 2308 Australia.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Verrills
authors.affiliation: Faculty of Pharmacy University of Sydney. NSW 2006 Australia.
authors.forename: Alaina J
authors.initials: AJ
authors.lastname: Ammit
mesh_terms: D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D013997:Time Factors; D051816:Tristetraprolin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; D019319:Okadaic Acid; D020928:Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2