Cyclooxygenase-2 and tissue inhibitor of matrix metalloproteinases-1 confer the antimigratory effect of cannabinoids on human trabecular meshwork cells.
Cannabinoids have received considerable attention as potential antiglaucomatous drugs. Recently, prostaglandins (PG) have been suggested to contribute to this effect. Within the factors conferring the development of glaucoma, depletion of the aqueous humor outflow-regulating trabecular meshwork (TM) cells elicited by migration from the outflow system is considered to play a pivotal role. This study therefore investigates the impact of two cannabinoids, Delta(9)-tetrahydrocannabinol (THC) and R(+)-methanandamide (MA), on the migration of human TM cells and the involvement of the PG-synthesizing enzyme cyclooxygenase-2 (COX-2) and one of its potential downstream targets, the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), to this response. Using Boyden chamber assays cannabinoids were shown to elicit an antimigratory effect that was reversed by antagonists for CB(1) as well as CB(2) receptors and accompanied by upregulation of COX-2 and TIMP-1 expression and PGE(2) synthesis. Knockdown of cannabinoid-induced COX-2 or TIMP-1 expression by siRNA or inhibition of COX-2 activity by NS-398 led to a significant suppression of this antimigratory action. Migration was also diminished by the major COX-2 product PGE(2) and by recombinant TIMP-1. Experiments using selective E prostanoid (EP) receptor agonists and antagonists revealed that decreased migration by PGE(2), THC and MA was mediated via EP(2) and EP(4) receptors. Finally, the cannabinoid-mediated increases of TIMP-1 levels were abolished by NS-398, and PGE(2) was shown to elicit a concentration-dependent increase of TIMP-1. Collectively, this data demonstrate a COX-2-dependent upregulation of TIMP-1 conferring the antimigratory action of cannabinoids. A decreased migration reducing TM cell loss in glaucoma might be involved in the antiglaucomatous action of cannabinoids.
Ramer
Robert
R
Institute of Toxicology and Pharmacology, University of Rostock, Schillingallee 70, D-18057 Rostock, Germany.
Hinz
Burkhard
B
D001095:Arachidonic Acids / Q000494:pharmacology*; D002461:Cell Line, Transformed; D002464:Cell Migration Inhibition / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D013759:Dronabinol / Q000494:pharmacology*; D006801:Humans; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*; D014129:Trabecular Meshwork / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D001095:Arachidonic Acids; D019715:Tissue Inhibitor of Metalloproteinase-1; C088155:methanandamide; D013759:Dronabinol; D051546:Cyclooxygenase 2