The regulation of EN-RAGE (S100A12) gene expression in human THP-1 macrophages.
EN-RAGE is a ligand for the receptor for advanced glycation end products (RAGE) and may be involved in the development of diabetic macro- and micro-angiopathy. This study is designed to investigate the regulation of EN-RAGE gene expression in human macrophages. The amounts of EN-RAGE mRNA were measured in cultured human THP-1 macrophages after treatment with various stimuli known to modulate atherosclerosis. First, interleukin-6 (IL-6), a proinflammatory cytokine, increased the level of EN-RAGE mRNA by approximately 2-fold in a time- and a dose-dependent fashion. EN-RAGE protein was detected in the cultured medium and increased significantly by the addition of IL-6. The induction was abolished by pretreatment with the JAK kinase inhibitor and cycloheximide, but not with the MEK kinase inhibitor. Second, pioglitazone (PIO), a thiazolidinedione, decreased the level of EN-RAGE mRNA by approximately 25% of the basal in a time- and a dose-dependent fashion. Pioglitazone also inhibited the induction of EN-RAGE mRNA by IL-6. These results indicate the production of EN-RAGE is induced by IL-6 through de novo protein synthesis via the JAK-STAT kinase pathway and inhibited by the activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) in human macrophages.
Hasegawa
Takamasa
T
Department of Medicine II, Kansai Medical University, 10-15 Fumizono-cho, Osaka 570-8507, Moriguchi, Japan.
Kosaki
Atsushi
A
Kimura
Tatsuji
T
Matsubara
Hiroaki
H
Mori
Yasukiyo
Y
Okigaki
Mitsuhiko
M
Masaki
Hiroya
H
Toyoda
Nagaoki
N
Inoue-Shibata
Megumi
M
Kimura
Yutaka
Y
Nishikawa
Mitsushige
M
Iwasaka
Toshiji
T
D000704:Analysis of Variance; D001483:Base Sequence; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D009418:S100 Proteins / Q000096:biosynthesis / Q000235:genetics*; D000067616:S100A12 Protein; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists; D014407:Tumor Cells, Cultured
D015850:Interleukin-6; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077205:Pioglitazone