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.
Stebulis
Judith A
JA
UMass Memorial Medical Center, Rheumatology Division, 119 Belmont Street, Worcester, MA 01605, USA. judith.stebulis@umassmed.edu
Johnson
David R
DR
Rossetti
Ronald G
RG
Burstein
Sumner H
SH
Zurier
Robert B
RB
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