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JNK inhibitor SP600125 reduces COX-2 expression by attenuating mRNA in activated murine J774 macrophages

Riina Nieminen1, Aleksi Lahti, Ulla Jalonen

  • 1The Immunopharmacology Research Group, University of Tampere Medical School, and Tampere University Hospital, Research Unit, FIN-33014, Tampere, Finland.

International Immunopharmacology
|April 29, 2006
PubMed

Insights

The c-Jun NH2-terminal kinase (JNK) pathway regulates cyclooxygenase-2 (COX-2) expression in macrophages. JNK activation by lipopolysaccharide (LPS) increases prostaglandin E2 production, suggesting JNK influences COX-2 mRNA stability.

Area of Science:

  • Immunology
  • Molecular Biology
  • Biochemistry

Background:

  • Cyclooxygenase-2 (COX-2) is a key enzyme in prostaglandin synthesis, upregulated during inflammation.
  • The precise signaling pathways controlling COX-2 induction remain incompletely understood.

Purpose of the Study:

  • To investigate the role of c-Jun NH2-terminal kinase (JNK), a mitogen-activated protein kinase (MAPK), in lipopolysaccharide (LPS)-induced COX-2 expression and prostaglandin E2 (PGE2) production in murine J774 macrophages.

Main Methods:

  • Activation of JNK by LPS in J774 macrophages.
  • Treatment with SP600125, a specific JNK inhibitor, to assess its effects on COX-2 protein and mRNA levels, and PGE2 production.
  • Assessment of JNK's role in cycloheximide-induced COX-2 expression.

Main Results:

  • LPS induced transient JNK activation, followed by increased COX-2 expression and PGE2 production.
  • SP600125 inhibited LPS-induced COX-2 protein levels and PGE2 production, with minimal effect on early COX-2 mRNA levels but significant reduction at later time points, indicating faster mRNA decay.
  • SP600125 also inhibited cycloheximide-induced COX-2 expression.

Conclusions:

  • The JNK pathway is implicated in the upregulation of COX-2 expression.
  • JNK may regulate COX-2 expression primarily through mechanisms affecting mRNA stability rather than transcriptional control.

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