Production of interleukin-1 and tumour necrosis factor from stimulated human monocytes is inhibited by a new series of pyridinyl-imidazole compounds. Using radiolabelled and radio-photoaffinity-labelled chemical probes, the target of these compounds was identified as a pair of closely related mitogen-activated protein kinase homologues, termed CSBPs. Binding of the pyridinyl-imidazole compounds inhibited CSBP kinase activity and could be directly correlated with their ability to inhibit cytokine production, suggesting that the CSBPs are critical for cytokine production.

Thus, these novel compounds offer a new disease modifying therapy for arthritis and the results also suggest that inhibition of TNF alpha production may contribute, at least in part, to their anti-arthritic activity.

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Exposure of human monocytes (HM) to E. coli lipopolysaccharide (LPS) results in measurable production of both IL-1 beta and TNF alpha in culture supernatants. It has previously been reported that the elevation of cAMP levels in HM selectively suppresses the LPS-induced TNF alpha but not IL-1 beta production. In this study we investigated whether the novel anti-inflammatory drug, SK&F 86002 [5-4(-pyridyl)-6(4-fluorophenyl)-2,3-dihydroimidazole(2,1-b)thi azol] and related analogs of the pyridinyl imidazole class, inhibit IL-1 and TNF production via a cAMP-dependent mechanism. These compounds, when added together with LPS result in inhibition of IL-1 and TNF production with equal-rank-order potency. Although the pyridinyl imidazole compounds were found to be generally weak phosphodiesterase inhibitors, they did not affect cAMP levels in HM, alone or in the presence of LPS. In contrast, PGE2, which significantly elevated intracellular cAMP levels, inhibited TNF but not IL-1 production at the transcriptional level. Taken together, these results suggest that the pyridinyl imidazoles inhibit the production of IL-1 beta and TNF alpha through pathways independent of cAMP elevating mechanisms.

Abstract. The effects of bicyclic imidazoles on human monocyte and endothelial cell cytokine production were examined. These compounds constitute the CSAID TM class of anti-inflammatories and are inhibitors of cytokine biosynthesis. The bicyclic imidazoles differ from glucocorticoids and phosphodiesterase inhibitors in their chemical structure as well as pharmacological profile. At optimal concentrations of LPS (50 ng/ml), SK&F 86002, a prototypic compound, inhibited IL-1 and TNF but not g-CSF or IRAP production in human monocytes. At suboptimal concentrations of LPS (50 pg/ml), IL-6 and IL-8 production were also inhibited. Inhibition of cytokine biosynthesis was stimulus independent. For example, induction of IL-1 or TNF expression by phosphatase 1 and 2A inhibitors (Okadaic acid or Calyculin A) and Vitamin D3-dependent induction of IL-1 or TNF was also inhibited. In addition, IL-8 production, but not ICAM/E-Selectin expression in IL-l-stimulated HUVEC, was inhibited at similar ICsos. Taken together, the bicyclic imidazoles inhibit cytokine production selectively in a stimulus and cell type independent manner.