- Title
- Basal protein phosphatase 2A activity restrains cytokine expression: role for MAPKs and tristetraprolin
- Creator
- Rahman, Md. Mostafizur; Rumzhum, Nowshin N.; Morris, Jonathan C.; Clark, Andrew R.; Verrills, Nicole M.; Ammit, Alaina J.
- Relation
- NHMRC.1025637 http://purl.org/au-research/grants/nhmrc/1025637
- Relation
- Scientific Reports Vol. 5, p. 1-16
- Publisher Link
- http://dx.doi.org/10.1038/srep10063
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2015
- Description
- 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.
- Subject
- inflammation; asthma; PP2A; cell signalling; proteins; respiratory distress syndrome
- Identifier
- http://hdl.handle.net/1959.13/1339741
- Identifier
- uon:28327
- Identifier
- ISSN:2045-2322
- Rights
- This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material.
- Language
- eng
- Full Text
- Reviewed
- Hits: 4802
- Visitors: 2911
- Downloads: 322
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT02 | Publisher version (open access) | 2 MB | Adobe Acrobat PDF | View Details Download |