Treatment with Y-40138, a multiple cytokine production modulator, inhibits lipopolysaccharide- or tumour necrosis factor-α-induced production of pro-inflammatory cytokines and augments interleukin-10

Abstract

N-[1-(4-[4-(pyrimidin-2-yl)piperazin-1-yl]methyl phenyl)cyclopropyl] acetamide.HCl (Y-40138) suppresses liver injury in concanavalin A- and d-galactosamine/lipopolysaccharide (LPS)-induced mouse hepatitis models. However, the mechanism of action of Y-40138 has not been fully investigated. In this study, we examined the effect of Y-40138 on cytokine production in mice. Cytokine production was induced by intraperitoneal injection of LPS (0.5 mg kg−1) or intravenous injection of recombinant mouse tumour necrosis factor (TNF)-α (10μg mouse−1) in BALB/c mice. TNF-α and interleukin (IL)-10 reached maximum levels 1.5 h after the LPS injection. IL-12 and interferon-γ (IFN-γ) reached maximum levels 3 to 9 h after the injection. When Y-40138 was orally administered 30 min prior to the injection, it inhibited TNF-α, IL-12 and IFN-γ production and augmented IL-10 production. Y-40138 also inhibited IL-12 production and augmented IL-10 production in TNF-α-stimulated mice. In IL-10 knockout mice, Y-40138 inhibited TNF-α and IL-12 production 1.5h after the LPS injection but not after 3 h or later, unlike in wild mice. In addition, TNF-α production was inhibited by Y-40138 at concentrations that could not augment IL-10 production. These data suggest that Y-40138 modulates pro-inflammatory cytokine production by both IL-10-dependent and -independent mechanisms.