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R.B. · 05-19-2006, 04:59 PM

NSAIDs inhibit the serine-threonine kinase p21-activated protein kinase 1 (Pak1)

Is the implication that P21 is inflamation related.

How does impact of omega sixes and three six balance on inflamatory pathways fit in?

RB

1: Blood. 2005 Mar 1;105(5):2042-8. Epub 2004 Oct 28. Related Articles, Links
Click here to read
Nonsteroidal anti-inflammatory drugs inhibit a Fyn-dependent pathway coupled to Rac and stress kinase activation in TCR signaling.

Paccani SR, Patrussi L, Ulivieri C, Masferrer JL, D'Elios MM, Baldari CT.

Department of Evolutionary Biology, University of Siena, Siena, Via Aldo Moro 2, 53100 Siena, Italy.

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.

PMID: 15514010 [PubMed - indexed for MEDLINE]

05-19-2006, 04:59 PM	#5
R.B. Senior Member Join Date: Mar 2006 Posts: 1,843	NSAIDs inhibit the serine-threonine kinase p21-activated protein kinase 1 (Pak1) NSAIDs inhibit the serine-threonine kinase p21-activated protein kinase 1 (Pak1) Is the implication that P21 is inflamation related. How does impact of omega sixes and three six balance on inflamatory pathways fit in? RB 1: Blood. 2005 Mar 1;105(5):2042-8. Epub 2004 Oct 28. Related Articles, Links Click here to read Nonsteroidal anti-inflammatory drugs inhibit a Fyn-dependent pathway coupled to Rac and stress kinase activation in TCR signaling. Paccani SR, Patrussi L, Ulivieri C, Masferrer JL, D'Elios MM, Baldari CT. Department of Evolutionary Biology, University of Siena, Siena, Via Aldo Moro 2, 53100 Siena, Italy. 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. PMID: 15514010 [PubMed - indexed for MEDLINE]