Compounds that increase or mimic cyclic adenosine monophosphate enhance tristetraprolin degradation in lipopolysaccharide-treated murine j774 macrophages.
Tristetraprolin (TTP) is a trans-acting factor that can regulate mRNA stability by binding to the cis-acting AU-rich element (ARE) in the 3'-untranslated region in mRNAs of certain transiently expressed genes. The best-studied target of TTP is tumor necrosis factor (TNF)-. By binding to ARE, TTP increases the degradation of TNF-alpha mRNA, thereby reducing the expression of TNF-alpha. We examined the effects of cAMP analogs and the cAMP-elevating agents forskolin and beta2-agonists on lipopolysaccharide (LPS)-induced TTP mRNA and protein expression by quantitative real-time reverse transcriptase-polymerase chain reaction and Western blotting in activated macrophages. All of these agents caused a slight increase in LPS-induced expression of TTP mRNA. However, TTP protein levels were significantly reduced when the cells were treated with the combination of LPS and cAMP-elevating agent compared with LPS alone. Proteasome inhibitors MG132 (N-[(phenylmethoxy)-carbonyl]-L-leucyl-N-[(1S)-1-formyl-3-methylbutyl]-L-leucinamide) and lactacystin increased TTP protein levels and abolished the effects of cAMP-enhancing compounds on TTP protein levels. The results suggest that mediators and drugs that enhance intracellular cAMP reduce TTP expression in macrophages exposed to inflammatory stimuli by increasing TTP degradation through the proteasome pathway.
Jalonen
Ulla
U
The Immunopharmacology Research Group, Medical School, University of Tampere and Research Unit, Tampere University Hospital, Tampere, Finland.
Paukkeri
Erja-Leena
EL
Moilanen
Eeva
E
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D061988:Proteasome Inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D051816:Tristetraprolin / Q000096:biosynthesis* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D008070:Lipopolysaccharides; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497553:Zfp36 protein, mouse; D005576:Colforsin; D000242:Cyclic AMP; D048051:p38 Mitogen-Activated Protein Kinases