Cytokines suppress adipogenesis and PPAR-gamma function through the TAK1/TAB1/NIK cascade.
Pluripotent mesenchymal stem cells in bone marrow differentiate into adipocytes, osteoblasts and other cells. Balanced cytodifferentiation of stem cells is essential for the formation and maintenance of bone marrow; however, the mechanisms that control this balance remain largely unknown. Whereas cytokines such as interleukin-1 (IL-1) and tumour-necrosis factor-alpha (TNF-alpha) inhibit adipogenesis, the ligand-induced transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma), is a key inducer of adipogenesis. Therefore, regulatory coupling between cytokine- and PPAR-gamma-mediated signals might occur during adipogenesis. Here we show that the ligand-induced transactivation function of PPAR-gamma is suppressed by IL-1 and TNF-alpha, and that this suppression is mediated through NF-kappaB activated by the TAK1/TAB1/NF-kappaB-inducing kinase (NIK) cascade, a downstream cascade associated with IL-1 and TNF-alpha signalling. Unlike suppression of the PPAR-gamma transactivation function by mitogen-activated protein kinase-induced growth factor signalling through phosphorylation of the A/B domain, NF-kappaB blocks PPAR-gamma binding to DNA by forming a complex with PPAR-gamma and its AF-1-specific co-activator PGC-2. Our results suggest that expression of IL-1 and TNF-alpha in bone marrow may alter the fate of pluripotent mesenchymal stem cells, directing cellular differentiation towards osteoblasts rather than adipocytes by suppressing PPAR-gamma function through NF-kappaB activated by the TAK1/TAB1/NIK cascade.
Suzawa
Miyuki
M
Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Takada
Ichiro
I
Yanagisawa
Junn
J
Ohtake
Fumiaki
F
Ogawa
Satoko
S
Yamauchi
Toshimasa
T
Kadowaki
Takashi
T
Takeuchi
Yasuhiro
Y
Shibuya
Hiroshi
H
Gotoh
Yukiko
Y
Matsumoto
Kunihiro
K
Kato
Shigeaki
S
D048868:Adaptor Proteins, Signal Transducing; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology; D016207:Cytokines / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D015699:HIV Envelope Protein gp120 / Q000502:physiology*; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D051379:Mice; D010957:Plasmids; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology*; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000502:physiology*; D000077288:Troglitazone; D000097782:NF-kappaB-Inducing Kinase; D000099151:MAP Kinase Kinase Kinase 7
D048868:Adaptor Proteins, Signal Transducing; D002839:Chromans; D016207:Cytokines; D015699:HIV Envelope Protein gp120; D020930:MAP Kinase Kinase Kinases; D017346:Protein Serine-Threonine Kinases; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077288:Troglitazone; D000097782:NF-kappaB-Inducing Kinase; D000099151:MAP Kinase Kinase Kinase 7; C486300:TAB1 protein, human