Activation of LXRs using the synthetic agonist GW3965 represses the production of pro-inflammatory cytokines by murine mast cells.
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 representative 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 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-1α and IL-1β, 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 attenuates 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.
Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan; Allergy and Immunology Group, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan. Electronic address: nunomura.satoshi@nihon-u.ac.jp.
Satoshi
S
Nunomura
Allergy and Immunology Group, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan.
Yoshimichi
Y
Okayama
Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
Kenji
K
Matsumoto
Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
Noriko
N
Hashimoto
Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan.
Kaori
K
Endo-Umeda
Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan.
Tadashi
T
Terui
Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan.
Makoto
M
Makishima
Allergy and Immunology Group, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan; Department of Microbiology, Nihon University School of Medicine, Tokyo, Japan; Asahi Hospital, Chiba, Japan.
Chisei
C
Ra
D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D000071518:Liver X Receptors; D008407:Mast Cells / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017455:Receptors, IgE / Q000819:agonists / Q000378:metabolism
D001565:Benzoates; D001596:Benzylamines; D016207:Cytokines; C473027:GW 3965; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D017455:Receptors, IgE; D007073:Immunoglobulin E
Cell degranulation; Cytokines; IgE receptor; Liver X receptor; Mast cells