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-alpha (TNF-alpha) 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-alpha and GM-CSF. We examined the role of beta(2)-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 kappaB (NF-kappaB) seemed not to play any role. This mechanism may, at least in part, explain the anti-inflammatory effects which beta(2)-agonists have been reported to have in macrophages.
Jalonen
Ulla
U
The Immunopharmacology Research Group, Medical School, University of Tampere, and Research Unit, Tampere University Hospital, 33014, Tampere, Finland.
Leppänen
Tiina
T
Kankaanranta
Hannu
H
Moilanen
Eeva
E
D000420:Albuterol / Q000494:pharmacology*; D000818:Animals; D015152:Blotting, Northern; D003994:Bucladesine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D020871:RNA Stability / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000378:metabolism; D051816:Tristetraprolin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016601:RNA-Binding Proteins; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D003994:Bucladesine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000420:Albuterol