NOVEL DITERPENOID LABDANE FROM SIDERITIS-JAVALAMBRENSIS INHIBITS EICOSANOID GENERATION FROM STIMULATED MACROPHAGES BUT ENHANCES ARACHIDONATE RELEASE

The diterpenoid ent-8 alpha-hydroxy-labda-13(16),14-dien (''labdane F2 '') was obtained from an anti inflammatory extract of Sideritis javala mbrensis. Labdane F2 inhibited prostaglandin E(2) generation in cultur ed mouse peritoneal macrophages, treated with zymosan, ionophore A2318 7, or arachidonic acid itself, and in J774 macrophage-like cells activ ated by bacterial lipopolysaccharide (LPS). The mechanism was investig ated by prelabelling the macrophages with radiolabelled arachidonic ac id or oleic acid, followed by cell activation in the presence or absen ce of nontoxic concentrations of labdane F2. Surprisingly, under those conditions in which reduced PGE(2) generation was observed, labdane F 2 consistently enhanced the release of labelled fatty acid, in a manne r similar to that displayed by thimerosal, a known acyl-CoA:lysolecith in transferase inhibitor. Labdane F2, therefore, appears to possess 2 mutually opposing actions on the eicosanoid system in macrophages: pot entiation of delivery of substrate following cell activation, followed by inhibition of conversion of substrate to product. rc was also foun d 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 labd ane possesses a diverse array of effects impinging on enzyme pathways involved in eicosanoid generation and other inflammatory pathways in m acrophages.