Dexamethasone Destabilizes Cyclooxygenase 2 mRNA by Inhibiting Mitogen-Activated Protein Kinase p38

Abstract

The stability of cyclooxygenase 2 (Cox-2) mRNA is regulated positively by proinflammatory stimuli acting through mitogen-activated protein kinase (MAPK) p38 and negatively by anti-inflammatory glucocorticoids such as dexamethasone. A tetracycline-regulated reporter system was used to investigate mechanisms of regulation of Cox-2 mRNA stability. Dexamethasone was found to destabilize ␤-globin-Cox-2 reporter mRNAs by inhibiting p38. This inhibition occurred at the level of p38 itself: stabilization of reporter mRNA by a kinase upstream of p38 was blocked by dexamethasone, while stabilization by a kinase downstream of p38 was insensitive to dexamethasone. Inhibition of p38 activity by dexamethasone was observed in a variety of cell types treated with different activating stimuli. Furthermore, inhibition of p38 was antagonized by the antiglucocorticoid RU486 and was delayed and actinomycin D sensitive, suggesting that ongoing glucocorticoid receptor-dependent transcription is required.

Anti-inflammatory functions of glucocorticoid-induced genes

“…Targets of such regulation include COX-2 (Chivers et al, 2006;Lasa et al, 2001;Newton et al, 1998;Ristimaki et al, 1996), TNF (Han et al, 1990;Kontoyiannis et al, 1999;Swantek et al, 1997), vascular endothelial growth factor (Gille et al, 2001), interferon β (Peppel et al, 1991), colony stimulating factor 2 (CSF2) (Bergmann et al, 2004;Tobler et al, 1992;Tran et al, 2005), IL-5 (Staples et al, 2003), IL-6 (Amano et al, 1993;Tobler et al, 1992), IL-1α and -1β (Amano et al, 1993;Lee et al, 1988), inducible nitric oxide synthase (Korhonen et al, 2002) and several chemokines (Berkman et al, 1995;Brach et al, 1992;Chang et al, 2001;Chaudhary and Avioli, 1996;Chivers et al, 2006;Mukaida et al, 1991;Poon et al, 1999;Stellato et al, 1999;Tobler et al, 1992). The majority of these mRNAs have in common the presence of adenylate/uridylate-rich elements (AREs) in their 3' untranslated regions (UTRs).…”

How Do Corticosteroids Work in Asthma?

“…Corticosteroids may inhibit AP-1 and NF-B via an inhibitory effect on c-Jun N-terminal kinases, which activate these transcription factors (37,38). Corticosteroids reduce the stability of mRNA for some inflammatory genes, such as cyclooxygenase-2, through an inhibitory action on another MAP kinase, p38 MAP kinase (39). This inhibitory effect is mediated via the induction of a potent endogenous inhibitor of p38 MAP kinase called MAP kinase phosphatase-1 (40).…”

Phosphatidylinositol 3-Kinase Activity Negatively Regulates Stability of Cyclooxygenase 2 mRNA

“…p38 activity has been linked to regulation of cytokine mRNA stability via its inhibitory actions on the mRNA destabilizing protein tristetraprolin (29). More specifically, p38 activation has been linked to COX2 mRNA stability (27,30,31).…”