title: Nonsteroidal anti-inflammatory drugs suppress T-cell activation by inhibiting p38 MAPK induction.
abstract: 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.
authors.affiliation: Department of Evolutionary Biology, University of Siena, Via Mattioli 4, 53100 Siena, Italy.
authors.forename: Silvia Rossi
authors.initials: SR
authors.lastname: Paccani
authors.forename: Marianna
authors.initials: M
authors.lastname: Boncristiano
authors.forename: Cristina
authors.initials: C
authors.lastname: Ulivieri
authors.forename: Mario Milco
authors.initials: MM
authors.lastname: D'Elios
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Del Prete
authors.forename: Cosima T
authors.initials: CT
authors.lastname: Baldari
mesh_terms: 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
chemical_list: 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