INHIBITION OF INTERLEUKIN-1 (IL-1) AND TUMOR-NECROSIS-FACTOR (TNF) PRODUCTION BY PYRIDINYL IMIDAZOLE COMPOUNDS IS INDEPENDENT OF CAMP ELEVATING MECHANISMS

Exposure of human monocytes (HM) to E. coli lipopolysacharide (LPS) re sults in measurable production of both IL-1beta and TNFalpha in cultur e supernatants. It has previously been reported that the elevation of cAMP levels in HM selectively suppresses the LPS-induced TNFalpha but not IL-1beta production. In this study we investigated whether the nov el anti-inflammatory drug, SK&F 86002 -fluorophenyl)-2,3-dihydroimidaz ole(2,1-b)thiazol] and related analogs of the pyridinyl imidazole clas s, inhibit IL-1 and TNF production via a cAMP-dependent mechanism. The se compounds, when added together with LPS result in inhibition of IL- 1 and TNF production with equal-rank-order potency. Although the pyrid inyl imidazole compounds were found to be generally weak phosphodieste rase inhibitors, they did not affect cAMP levels in HM, alone or in th e presence of LPS. In contrast, PGE2, which significantly elevated int racellular cAMP levels, inhibited TNF but not IL-1 production at the t ranscriptional level. Taken together, these results suggest that the p yridinyl imidazoles inhibit the production of IL-1beta and TNFalpha th rough pathways independent of cAMP elevating mechanisms.