Salbutamol increases tristetraprolin expression in macrophages

Tristetraprolin (TTP) is a tandem zinc finger protein that can bind to AU-rich elements (AREs) in the 3′-untranslated regions (3′-UTR) in mRNAs of transiently expressed genes, e.g. tumor necrosis factor-α (TNF-α) and granulocyte macrophage colony-stimulating factor (GM-CSF). TTP increases the turnover rate of the target mRNAs, thereby reducing, for example, the expression of TNF-α and GM-CSF. We examined the role of β2-agonists, cAMP analogs, and forskolin (an activator of adenylate cyclase) on TTP mRNA and protein expression by quantitative real-time RT-PCR and Western blotting in J774 murine macrophages and THP-1 human macrophages. All of these agents increased TTP expression. A nonspecific inhibitor of phosphodiesterases (PDEs) 3-isobutyl-1-methylxanthine (IBMX) and type IV PDE-inhibitor rolipram further enhanced the increase in TTP expression levels, suggesting a cAMP-mediated effect. A possible mediator of these effects is transcription factor activator protein 2 (AP-2), whereas nuclear factor κB (NF-κB) seemed not to play any role. This mechanism may, at least in part, explain the anti-inflammatory effects which β2-agonists have been reported to have in macrophages.