Nonsteroidal anti-inflammatory drugs inhibit a Fyn-dependent pathway coupled to Rac and stress kinase activation in TCR signaling.
In addition to their anti-inflammatory properties, nonsteroidal anti-inflammatory drugs (NSAIDs) harbor immunosuppressive activities related to their capacity both to inhibit cyclooxygenases (COXs) and to act as peroxisome proliferator-activated receptor (PPAR) ligands. We have previously shown that the stress-activated kinase p38 is a selective target of NSAIDs in T cells. Here we have investigated the effect of NSAIDs on the signaling pathway triggered by the T-cell antigen receptor (TCR) and leading to stress kinase activation. The results show that nonselective and COX-1-selective NSAIDs also block activation of the stress kinase c-Jun N-terminal kinase (JNK) and that prostaglandin-E2 (PGE2) reverses this block and enhances TCR-dependent JNK activation. Analysis of the activation state of the components upstream of p38 and JNK showed that NSAIDs inhibit the serine-threonine kinase p21-activated protein kinase 1 (Pak1) and the small guanosine 5'-triphosphatase (GTPase) Rac, as well as the Rac-specific guanine nucleotide exchanger, Vav. Furthermore, activation of Fyn, which controls Vav phosphorylation, is inhibited by NSAIDs, whereas activation of lymphocyte-specific protein tyrosine kinase (Lck) and of the Lck-dependent tyrosine kinase cascade is unaffected. Accordingly, constitutively active Fyn reverses the NSAID-dependent stress kinase inhibition. The data identify COX-1 as an important early modulator of TCR signaling and highlight a TCR proximal pathway selectively coupling the TCR to stress kinase activation.
Paccani
Silvia Rossi
SR
Department of Evolutionary Biology, University of Siena, Siena, Via Aldo Moro 2, 53100 Siena, Italy.
Patrussi
Laura
L
Ulivieri
Cristina
C
Masferrer
Jaime L
JL
D'Elios
Mario Milco
MM
Baldari
Cosima T
CT
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D051545:Cyclooxygenase 1; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins; D015232:Dinoprostone