Thalidomide destabilizes cyclooxygenase-2 mRNA by inhibiting p38 mitogen-activated protein kinase and cytoplasmic shuttling of HuR

Eur J Pharmacol. 2007 Mar 8;558(1-3):14-20. doi: 10.1016/j.ejphar.2006.11.060. Epub 2006 Dec 8.

Abstract

We investigated the effect of thalidomide on transcriptional and post-transcriptional cyclooxygenase-2 (COX-2) expression, including a pathway leading to COX-2 mRNA destabilization. We found that thalidomide inhibited the interleukin-1beta (IL-1beta)-mediated induction of COX-2 protein and mRNA in Caco-2 cells. Transient transfection with a COX-2 promoter construct demonstrated that thalidomide did not affect IL-1beta-induced transcriptional activation of COX-2, although it did decrease the stability of COX-2 mRNA and suppress IL-1beta-induced cytoplasmic shuttling of an mRNA stabilizing protein, HuR. Thalidomide also suppressed IL-1beta-induced p38 mitogen-activated protein kinase (MAPK) activation, while a p38 MAPK inhibitor destabilized COX-2 mRNA and the cytoplasmic shuttling of HuR induced by IL-1beta. These data suggest that one of the molecular mechanisms of thalidomide may be destabilization of COX-2 mRNA through inhibition of cytoplasmic shuttling of HuR and p38 MAPK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Surface / metabolism*
  • Caco-2 Cells
  • Cyclooxygenase 2 / genetics*
  • Cytoplasm / metabolism*
  • ELAV Proteins
  • ELAV-Like Protein 1
  • Humans
  • Imidazoles / pharmacology
  • Interleukin-1beta / pharmacology
  • Protein Transport / drug effects
  • Pyridines / pharmacology
  • RNA Stability / drug effects*
  • RNA-Binding Proteins / metabolism*
  • Thalidomide / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*

Substances

  • Antigens, Surface
  • ELAV Proteins
  • ELAV-Like Protein 1
  • ELAVL1 protein, human
  • Imidazoles
  • Interleukin-1beta
  • Pyridines
  • RNA-Binding Proteins
  • Thalidomide
  • Cyclooxygenase 2
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580