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.

ROSSI PACCANI, S., Patrussi, L., Ulivieri, C., Masferrer, J.L., D'Elios, M.M., Baldari, C. (2005). Nonsteroidal anti-inflammatory drugs inhibit a Fyn dependent pathway coupled to Rac and stress kinase activation in TCR signaling. BLOOD, 105(5), 2042-2048 [10.1182/blood-2004-04-1299].

Nonsteroidal anti-inflammatory drugs inhibit a Fyn dependent pathway coupled to Rac and stress kinase activation in TCR signaling

ROSSI PACCANI, SILVIA;PATRUSSI, LAURA;ULIVIERI, CRISTINA;D'ELIOS M. M.;BALDARI, COSIMA
2005-01-01

Abstract

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.
2005
ROSSI PACCANI, S., Patrussi, L., Ulivieri, C., Masferrer, J.L., D'Elios, M.M., Baldari, C. (2005). Nonsteroidal anti-inflammatory drugs inhibit a Fyn dependent pathway coupled to Rac and stress kinase activation in TCR signaling. BLOOD, 105(5), 2042-2048 [10.1182/blood-2004-04-1299].
File in questo prodotto:
File Dimensione Formato  
Paccani Blood 2005a .pdf

non disponibili

Tipologia: Post-print
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 206.77 kB
Formato Adobe PDF
206.77 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/21935
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo