In vitro inhibition of arachidonic acid metabolism by two novel retinoid analogs
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Ro 23-6457, (all-E)-3,7-dimethyl-9-[2-(trifluoromethyl)-6-(nonyloxy) phenyl]-2,4,6,8-nonatetraenoic acid, and Ro 23-2895, (all-E)-9-[2-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid, are two novel retinoid analogs which exhibit antiinflammatory activity in both the developing and the established rat adjuvant arthritis models . Here we investigated the effect of these two compounds on the production of arachidonic acid (AA) metabolites in twoin vitro test systems [i.e., Ca2+ ionophore A23187 (I)-stimulated resident rat peritoneal macrophages (MØ) and cytokine-stimulated human dermal fibroblasts (HDF)]. Both compounds, Ro 23-6457 and Ro 23-2895, significantly inhibited the release of14C-AA metabolites and the production of LTB4, PGE2, and 6-keto-PGF1α in I-stimulated MØ, at concentrations of 1–33 μM. Both compounds also inhibited the production of PGE2 in HDF stimulated by either rhuIL-1α or hu TNFα at concentrations of 1×10−5 to 1×10−7M. Ro 23-2895 was also a potent inhibitor of IL-1-induced collagenase production in rheumatoid synovial cells (IC50≈1 to 2.5×10−8M). The inhibitory profile of these novel compounds in these cell systems is therefore similar to that of other known antiinflammatory retinoids (e.g., all-trans- and 13-cis-retinoic acid). Inhibitory effects such as those described here might in part contribute to the antiinflammatory activity of these compoundsin vivo.
KeywordsArachidonic Acid PGE2 Retinoid Peritoneal Macrophage A23187
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