Ajulemic acid, a synthetic cannabinoid acid, induces an antiinflammatory profile of eicosanoids in human synovial cells.
OBJECTIVE
To better understand mechanisms whereby Ajulemic acid (AjA), a synthetic antiinflammatory cannabinoid, promotes resolution of acute and chronic inflammation in animal models, we investigated its influence on cyclooxygenase 2 (COX2) expression and eicosanoid production in human fibroblast-like synovial cells (FLS).


METHODS
FLS isolated from tissue obtained at joint replacement surgery or cultured from synovial fluid were treated for 60 min with AjA (10-30 microM), then stimulated with tumor necrosis factor alpha (TNFalpha). COX2 mRNA was measured by hybridization/colorimetric assay of whole cell lysates collected 4 h after stimulation. To determine effects on arachidonic acid release, FLS were incubated with (14)C-arachidonic acid for 20 h then treated with AjA (8-32 microM). Arachidonic acid release was measured by scintillation counting. Prostaglandins (PG) were measured by enzyme linked immunosorbent assay (ELISA) in cell supernatants collected 4 and 24 h after stimulation.


RESULTS
AjA increased the steady state levels of COX2 mRNA in and arachidonic acid release from FLS. Treatment of FLS with AjA increased 15-deoxy-delta(12,14)-PGJ(2) (15d-PGJ(2)) production in a concentration dependent manner, but did not affect PGE(2) production significantly.


CONCLUSIONS
The capacity of AjA to increase selectively and markedly 15d-PGJ(2), an eicosanoid which facilitates resolution of inflammation, suggests that AjA may have value as a therapeutic agent for the treatment of rheumatoid arthritis (RA) and other diseases characterized by acute and chronic inflammation.
UMass Memorial Medical Center, Rheumatology Division, 119 Belmont Street, Worcester, MA 01605, USA. judith.stebulis@umassmed.edu
Judith A
JA
Stebulis
David R
DR
Johnson
Ronald G
RG
Rossetti
Sumner H
SH
Burstein
Robert B
RB
Zurier
D000893:Anti-Inflammatory Agents; D016718:Arachidonic Acid / Q000096:biosynthesis; D015535:Arthritis, Psoriatic / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D015777:Eicosanoids / Q000378:metabolism*; D006801:Humans; D011453:Prostaglandins / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013582:Synovial Fluid / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D015777:Eicosanoids; D011453:Prostaglandins; D012333:RNA, Messenger; D016718:Arachidonic Acid; D013759:Dronabinol; D051546:Cyclooxygenase 2; C471849:lenabasum