PMID- 19318593 OWN - NLM STAT- MEDLINE DCOM- 20090623 LR - 20181201 IS - 1521-0103 (Electronic) IS - 0022-3565 (Linking) VI - 329 IP - 3 DP - 2009 Jun TI - Cyclooxygenase-2 induced by zymosan in human monocyte-derived dendritic cells shows high stability, and its expression is enhanced by atorvastatin. PG - 987-94 LID - 10.1124/jpet.108.149336 [doi] AB - Cyclooxygenase (COX)-2 is a central enzyme of arachidonic acid metabolism, and its modulation by statins may explain some of the myocardial protective effects of these drugs. Dendritic cells (DCs) play a central role in microbial defense and in atherogenesis, and COX-2 expression in DCs is important for their migration to lymph nodes and antibody response, thus explaining why prostaglandin E(2) is a main component of the cocktails used to prepare DCs for clinical applications. On this basis, we addressed the effect of atorvastatin (ATV) on the release of arachidonic acid and on the expression of COX-2 in human monocyte-derived DCs. Although ATV on its own lacked any effect on COX-2 protein induction expression, it enhanced the release of arachidonic acid, the expression of COX-2 protein, and the production of prostaglandin E(2) induced by the fungal wall extract zymosan, and to a lower extent the effect of peptidoglycan. The effect on COX-2 protein was observed mainly 24 h after stimulation by zymosan and was not reverted by mevalonate, thus pointing to an effect unrelated to cholesterol metabolism. It is noteworthy that COX-2 protein showed a great stability, with a t((1/2)) of approximately 12 h, which was enhanced in the presence of ATV. In view of the important role played by COX-2 on DC function, these data indicate that ATV, by enhancing COX-2 stability, may increase DC function after infectious bouts and also counteract some of the risks associated with sustained inhibition of COX-2. FAU - Alvarez, Yolanda AU - Alvarez Y AD - Instituto de Biologia y Genetica Molecular, Consejo Superior de Investigaciones Cientificas and Universidad de Valladolid, Spain. FAU - Municio, Cristina AU - Municio C FAU - Alonso, Sara AU - Alonso S FAU - San Roman, Jose Alberto AU - San Roman JA FAU - Sanchez Crespo, Mariano AU - Sanchez Crespo M FAU - Fernandez, Nieves AU - Fernandez N LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20090324 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 0 (Antigens, CD) RN - 0 (Heptanoic Acids) RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) RN - 0 (Peptidoglycan) RN - 0 (Pyrroles) RN - 27YG812J1I (Arachidonic Acid) RN - 9010-72-4 (Zymosan) RN - 98600C0908 (Cycloheximide) RN - A0JWA85V8F (Atorvastatin) RN - EC 1.14.99.1 (Cyclooxygenase 1) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - EC 3.1.1.4 (Phospholipases A2, Cytosolic) RN - K7Q1JQR04M (Dinoprostone) RN - S5UOB36OCZ (Mevalonic Acid) SB - IM MH - Antigens, CD/metabolism MH - Arachidonic Acid/metabolism/pharmacology MH - Atorvastatin MH - Cycloheximide/pharmacology MH - Cyclooxygenase 1/genetics/metabolism MH - Cyclooxygenase 2/genetics/*metabolism MH - Dendritic Cells/drug effects/*metabolism MH - Dinoprostone/metabolism MH - Gene Expression/*drug effects/genetics MH - Half-Life MH - Heptanoic Acids/*pharmacology MH - Humans MH - Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology MH - Kinetics MH - Mevalonic Acid/pharmacology MH - Peptidoglycan/pharmacology MH - Phospholipases A2, Cytosolic/metabolism MH - Pyrroles/*pharmacology MH - Zymosan/*pharmacology EDAT- 2009/03/26 09:00 MHDA- 2009/06/24 09:00 CRDT- 2009/03/26 09:00 PHST- 2009/03/26 09:00 [entrez] PHST- 2009/03/26 09:00 [pubmed] PHST- 2009/06/24 09:00 [medline] AID - jpet.108.149336 [pii] AID - 10.1124/jpet.108.149336 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2009 Jun;329(3):987-94. doi: 10.1124/jpet.108.149336. Epub 2009 Mar 24.