Received for publication July 27, 2005.
Revised December 1, 2005.
Accepted for publication December 1, 2005.

R(+)-methanandamide and other cannabinoids induce the expression of cyclooxygenase-2 and matrix metalloproteinases in human non-pigmented ciliary epithelial cells

Abstract

Prostaglandins (PGs) and matrix metalloproteinases (MMP) have been implicated in lowering intraocular pressure (IOP) by facilitating aqueous humor outflow. A possible role of cyclooxygenase-2 (COX-2) in this process was emphasized by findings showing an impaired COX-2 expression in the non-pigmented ciliary epithelium (NPE) of patients with primary open-angle glaucoma. Using human NPE cells, the present study therefore investigated the effect of the IOP-lowering cannabinoid R(+)-methanandamide (R(+)-MA) on the expression of COX-2 and different MMPs and tissue inhibitors of MMPs (TIMPs). R(+)-MA led to a concentration- and time-dependent increase of COX-2 mRNA expression. R(+)-MA-induced COX-2 expression was accompanied by time-dependent phosphorylations of p38 mitogen-activated protein kinase (MAPK) and p42/44 MAPK, and was abrogated by inhibitors of both pathways. Moreover, R(+)-MA increased the mRNA and protein expression of MMP-1, -3, -9 and TIMP-1, but not that of MMP-2 and TIMP-2. Inhibition of COX-2 activity with NS-398 was associated with a virtually complete suppression of R(+)-MA-induced MMP-9 and TIMP-1 expression. Consistent with this data, MMP-9 and TIMP-1 expression was also induced by PGE₂, a major COX-2 product. Two other COX-2-inducing cannabinoids, anandamide and ⁹-tetrahydrocannabinol, caused the same pattern of MMP- and TIMP expression as R(+)-MA both in the absence and presence of NS-398. Altogether, cannabinoids induce the production of several outflow-facilitating mediators in the human NPE. Our results further imply an involvement of COX-2-dependent PGs in MMP-9 and TIMP-1 expression. In conclusion, stimulation of intraocular COX-2 and MMP expression may represent a potential mechanism contributing to the IOP-lowering action of different cannabinoids.

Key words: R(+)-methanandamide, cannabinoid, cyclooxygenase-2, matrix metalloproteinases, non-pigmented ciliary epithelium, prostaglandins

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