Direct and indirect suppression of interleukin-6 gene expression in murine macrophages by nuclear orphan receptor REV-ERBα.
It is now evident that many nuclear hormone receptors can modulate target gene expression. REV-ERBα, one of the nuclear hormone receptors with the capacity to alter clock function, is critically involved in lipid metabolism, adipogenesis, and the inflammatory response. Recent studies suggest that REV-ERBα plays a key role in the mediation between clockwork and inflammation. The purpose of the current study was to investigate the role of REV-ERBα in the regulation of interleukin-6 (il6) gene expression in murine macrophages. REV-ERBα agonists, or overexpression of rev-erb α in the murine macrophage cell line RAW264 cells, suppressed the induction of il6 mRNA following a lipopolysaccharide (LPS) endotoxin challenge. Also, rev-erb α overexpression decreased LPS-stimulated nuclear factor κB (NFκB) activation in RAW264 cells. We showed that REV-ERBα represses il6 expression not only indirectly through an NFκB binding motif but also directly through a REV-ERBα binding motif in the murine il6 promoter region. Furthermore, peritoneal macrophages from mice lacking rev-erb α increased il6 mRNA expression. These data suggest that REV-ERBα regulates the inflammatory response of macrophages through the suppression of il6 expression. REV-ERBα may therefore be identified as a potent anti-inflammatory receptor and be a therapeutic target receptor of inflammatory diseases.
Department of Molecular Predictive Medicine and Sport Science, Kyorin University, School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan.
Shogo
S
Sato
Department of Molecular Predictive Medicine and Sport Science, Kyorin University, School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan.
Takuya
T
Sakurai
Department of Molecular Predictive Medicine and Sport Science, Kyorin University, School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan.
Junetsu
J
Ogasawara
Department of Molecular Predictive Medicine and Sport Science, Kyorin University, School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan.
Ken
K
Shirato
Department of Molecular Predictive Medicine and Sport Science, Kyorin University, School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan.
Yoshinaga
Y
Ishibashi
Department of Respiratory Medicine, National Hospital Organization, Ibarakihigashi National Hospital, 825 Terunuma, Tokai-mura, Naka-gun, Ibaraki 319-1113, Japan.
Shuji
S
Oh-ishi
Faculty of Human Sciences, Waseda University, 2-579-15 Mikajima, Tokorozawa, Saitama 359-1192, Japan.
Kazuhiko
K
Imaizumi
Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8573, Japan.
Shukoh
S
Haga
Graduate School of Medical Science, Kanazawa University, Kakumamachi, Kanazawa 920-1192, Japan.
Yoshiaki
Y
Hitomi
Faculty of Health and Sport Science, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan.
Tetsuya
T
Izawa
Faculty of Health and Sport Science, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan.
Yoshinobu
Y
Ohira
Department of Molecular Predictive Medicine and Sport Science, Kyorin University, School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan.
Hideki
H
Ohno
Department of Molecular Predictive Medicine and Sport Science, Kyorin University, School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan.
Takako
T
Kizaki
D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D015850:Interleukin-6 / Q000096:biosynthesis*; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D000093242:Interleukin-6 Inhibitors
D015850:Interleukin-6; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D000093242:Interleukin-6 Inhibitors; C498262:Nr1d1 protein, mouse; C577686:interleukin-6, mouse