A novel diterpenoid labdane from Sideritis javalambrensis inhibits eicosanoid generation from stimulated macrophages but enhances arachidonate release.
The diterpenoid ent-8alpha-hydroxy-labda-13(16),14-dien ("labdane F2") was obtained from an anti-inflammatory extract of Sideritis javalambrensis. Labdane F2 inhibited prostaglandin E2 generation in cultured mouse peritoneal macrophages, treated with zymosan, ionophore A23187, or arachidonic acid itself, and in J774 macrophage-like cells activated by bacterial lipopolysaccharide (LPS). The mechanism was investigated by prelabelling the macrophages with radiolabelled arachidonic acid or oleic acid, followed by cell activation in the presence or absence of nontoxic concentrations of labdane F2. Surprisingly, under those conditions in which reduced PGE2 generation was observed, labdane F2 consistently enhanced the release of labelled fatty acid, in a manner similar to that displayed by thimerosal a known acyl-CoA: lysolecithin transferase inhibitor. Labdane E2 therefore appears to possess 2 mutually opposing actions on the eicosanoid system in macrophages: potentiation of delivery of substrate following cell activation, followed by inhibition of conversion of substrate to product. It was also found that nontoxic concentrations of labdane F2 reduced the expression of the inducible isoforms of cyclooxygenase and nitric oxide synthase in LPS-treated J774 cells. Thus, this anti-inflammatory diterpenoid labdane possesses a diverse array of effects impinging on enzyme pathways involved in eicosanoid generation and other inflammatory pathways in macrophages.