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Dexamethasone destabilizes cyclooxygenase 2 mRNA by inhibiting mitogen-activated protein kinase p38

M Lasa1, M Brook, J Saklatvala

  • 1Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, Hammersmith, London W6 8LH, United Kingdom.

Molecular and Cellular Biology
|January 12, 2001
PubMed

Insights

Glucocorticoids like dexamethasone reduce cyclooxygenase 2 (Cox-2) mRNA stability by inhibiting the p38 mitogen-activated protein kinase (MAPK) pathway. This regulation requires ongoing glucocorticoid receptor-dependent transcription.

Area of Science:

  • Molecular Biology
  • Pharmacology
  • Cell Biology

Background:

  • Cyclooxygenase 2 (Cox-2) mRNA stability is crucial for inflammatory responses.
  • Proinflammatory stimuli stabilize Cox-2 mRNA via p38 MAPK.
  • Anti-inflammatory glucocorticoids, such as dexamethasone, negatively regulate Cox-2 mRNA stability.

Purpose of the Study:

  • To investigate the precise mechanisms by which dexamethasone regulates Cox-2 mRNA stability.
  • To elucidate the role of the p38 MAPK pathway in glucocorticoid-mediated Cox-2 mRNA regulation.

Main Methods:

  • Utilized a tetracycline-regulated reporter system to study beta-globin-Cox-2 reporter mRNAs.
  • Assessed the impact of dexamethasone on p38 MAPK activity and reporter mRNA stability.
  • Investigated the requirement for glucocorticoid receptor-dependent transcription.

Main Results:

  • Dexamethasone destabilized reporter mRNAs by inhibiting p38 MAPK activity.
  • This inhibition occurred at the level of p38 itself, upstream of downstream kinases.
  • Dexamethasone's effect was antagonized by RU486 and required ongoing transcription, indicating glucocorticoid receptor involvement.

Conclusions:

  • Dexamethasone negatively regulates Cox-2 mRNA stability through inhibition of p38 MAPK.
  • The mechanism involves direct inhibition of p38 and requires glucocorticoid receptor-dependent transcription.
  • Understanding this pathway offers insights into anti-inflammatory drug action.

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