Activation of LXRs using the synthetic agonist GW3965 represses the production of pro-inflammatory cytokines by murine mast cells

作者：Nunomura Satoshi^*; Okayama Yoshimichi; Matsumoto Kenji; Hashimoto Noriko; Endo Umeda Kaori; Terui Tadashi; Makishima Makoto; Ra Chisei

来源：Allergology International, 2015, 64: S11-S17.

DOI：10.1016/j.alit.2015.03.001

• Cell degranulation
• Cytokines
• IgE receptor
• Liver X receptor
• Mast cells

Background: The activation of liver X receptor (LXR) alpha or LXR beta negatively regulates the expression of pro-inflammatory genes in mammalian cells. We recently reported that 25-hydroxycholesterol, a representative LXR-activating oxysterol, suppresses IL-6 production in mouse mast cells (MCs) following its engagement of the high-affinity IgE receptor (Fc epsilon RI). 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 LXR alpha and LXR beta in the production of pro-inflammatory cytokines by murine bone marrow-derived MCs (BMMCs).
Methods: We prepared BMMCs from wild-type (WT), LXR alpha(-/-), and LXR alpha/beta(-/-) mice. Each group of BMMCs was pretreated with GW3965 and then stimulated with IgE+antigen (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-1 alpha and IL-1 beta, but not of IL-6, in the WT and LXR alpha(-/-) BMMCs stimulated with IgE+Ag. However, GW3965 treatment decreased the production of IL-1 alpha, IL-1 beta, and IL-6 in WT and LXR alpha(-/-) BMMCs upon stimulation with LPS, while the GW3965-mediated suppression of cytokine production was nearly absent from the LXR alpha/beta(-/-) BMMCs.
Conclusions: These findings demonstrate, for the first time, that the activation of LXRs by GW3965 attenuates the antigen-or LPS-induced production of pro-inflammatory cytokines, such as IL-1 alpha and IL-1 beta, in murine MCs and that LXR beta plays an important role in the LXR-mediated repression of cytokine production.

• 出版日期2015-9
• 单位河北医科大学