Nonsteroidal anti-inflammatory drugs suppress T-cell activation by inhibiting p38 MAPK induction.
In addition to antagonizing inflammation by inhibiting the activity of cyclooxygenases (COX), nonsteroidal anti-inflammatory drugs (NSAID) block T-cell activation. The immunosuppressant activity of NSAID correlates with their ability to block transcription factors required for the expression of inducible response genes triggered by T-cell antigen receptor (TCR) engagement. Whereas the inhibition of nuclear factor-kappaB by aspirin and sodium salicylate can be partly accounted for by their binding to IkappaB kinase-beta, the broad range of transcriptional targets of NSAID suggests that the products of COX activity might affect one or more among the early steps in the TCR-signaling cascade. Here we show that the inhibition of NF-AT activation by NSAID correlates with a selective inhibition of p38 MAP kinase induction. The suppression of TCR-dependent p38 activation by NSAID can be fully overcome by prostaglandin E(2), underlining the requirement for COX activity in p38 activation. Furthermore, the inhibition of COX-1 results in defective induction of the COX-2 gene, which behaves as an early TCR responsive gene. The data identify COX-1 and COX-2 as integral and sequential components of TCR signaling to p38 and contribute to elucidate the molecular basis of immunosuppression by NSAID.
Paccani
Silvia Rossi
SR
Department of Evolutionary Biology, University of Siena, Via Mattioli 4, 53100 Siena, Italy.
Boncristiano
Marianna
M
Ulivieri
Cristina
C
D'Elios
Mario Milco
MM
Del Prete
Gianfranco
G
Baldari
Cosima T
CT
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D004790:Enzyme Induction; D017930:Genes, Reporter; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases