抄録
Background: The activation of liver X receptor (LXR) α or LXRβ negatively regulates the expression of pro- inflammatory genes in mammalian cells. We recently reported that 25-hydroxycholesterol, a represen- tative LXR-activating oxysterol, suppresses IL-6 production in mouse mast cells (MCs) following its engagement of the high-affinity IgE receptor (FcεRI). This finding suggests that murine MCs express functional LXRs; however, the mechanisms underlying the LXR-dependent repression of the MC- mediated production of pro-inflammatory cytokines, including IL-6, are poorly understood. Therefore, we employed the synthetic LXR ligand GW3965 to examine the functions of LXRα and LXRβ in the production of pro-inflammatory cytokines by murine bone marrow-derived MCs (BMMCs).
Methods: We prepared BMMCs from wild-type (WT), LXRα−⁄−, and LXRα/β−⁄− mice. Each group of BMMCs was pretreated with GW3965 and then stimulated with IgEþantigen (Ag) or lipopolysaccharide (LPS). Cytokine production was then analyzed using specific ELISA kits.
Results: The activation of LXRs by GW3965 significantly attenuated the production of IL-1a and IL-1b, but not of IL-6, in the WT and LXRα−⁄− BMMCs stimulated with IgE+Ag. However, GW3965 treatment decreased the production of IL-1α, IL-1β, and IL-6 in WT and LXRα−⁄− BMMCs upon stimulation with LPS, while the GW3965-mediated suppression of cytokine production was nearly absent from the LXRα/β−⁄−BMMCs.
Conclusions: These findings demonstrate, for the first time, that the activation of LXRs by GW3965 at- tenuates the antigen- or LPS-induced production of pro-inflammatory cytokines, such as IL-1α and IL-1β, in murine MCs and that LXRβ plays an important role in the LXR-mediated repression of cytokine production.
