Abstract
Abstract Tumor necrosis factor (TNF)-α is a major cytokine produced by alveolar macrophages in response to pathogen associated molecular patterns such as LPS. TNF-α secretion is regulated at both transcriptional and post-transcriptional levels. Post-transcriptional regulation occurs by modulation of TNF-α mRNA stability via the binding of tristetraprolin (TTP) to the AU (adenosine/uridine)-rich elements (AREs) found in the 3’-untranslated region (3’-UTR) of TNF-α transcript. Phosphorylation plays important roles in modulating mRNA stability. Our results show that inhibition of PP2A by okadaic acid or siRNA significantly enhanced the stability of TNF-α mRNA. This result was associated with increased phosphorylation of p38 MAPK and MK-2. PP2A inhibition increased TTP phosphorylation and enhanced complex formation with chaperone protein 14-3-3. A functional consequence of TTP/14-3-3 complex formation appeared to be protection of TTP from dephosphorylation by inhibition of the binding of the catalytic unit of PP2A to phosphorylated TTP. Our data indicates that PP2A regulates TNF-α mRNA stability by modulating the phosphorylation state of members of the p38/MK-2/TTP pathway. This work was supported by grants from the National Institute of Health (7R01GM066839-03, to TPS).
Published Version
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