- Paper Report
- Open Access
NSAIDs inhibit p38 MAPK activation
- Cheryl Smythe1
© Biomed Central Ltd 2002
- Received: 6 February 2002
- Accepted: 20 February 2002
- Published: 20 February 2002
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity. Predominantly acting on macrophages and neutrophils, they have also been shown to suppress T-cell proliferation, expression of surface markers of activation and the secretion of cytokines. NSAIDs mediate these immunosuppressive effects by blocking transcription factors such as nuclear factor of activated T cells (NF-AT) and NF-?B. The effects of NSAIDs on components of the T-cell antigen receptor (TCR) signalling cascade proximal to transcription factor activation were investigated in this study.
Inhibition of TCR-mediated NF-AT activation was used to assess the effect of NSAIDs on T-cell signalling. COX-1 and COX-2 -selective NSAIDs, or Erk and p38 mitogen activated protein kinase inhibitors, all reduced NF-AT activation, although COX-2 selective inhibitors only partially inhibited it. TCR-induced p38 activity was inhibited by both nonselective and COX-1 specific NSAIDs, but not by COX-2 specific inhibitors. Erk activity, however, was unaffected by NSAIDs. NSAIDs did not inhibit lipopolysaccharide- or H2O2-induced p38 activation; therefore, they specifically affect TCR-mediated p38 activation. NSAIDs had no effect on reactive oxygen species (ROS), implying that their effect on TCR-mediated p38 activation was downstream of ROS generation. Furthermore NSAIDs had no effect on the Ca2+/calcineurin pathway that is also involved in the TCR activation of p38. Addition of prostaglandin E2 (PGE2) reversed NSAIDs inhibition of NF-AT activity, but did not overcome the inhibition of NF-AT activation by p38 inhibitors. Finally, inhibition of COX-1 blocked TCR-dependent COX-2 expression.
Luciferase assay, immunoblotting, measurement of reactive oxygen species, RT-PCR