title: Cytokines suppress adipogenesis and PPAR-gamma function through the TAK1/TAB1/NIK cascade.
abstract: 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.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Suzawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takada
authors.forename: Junn
authors.initials: J
authors.lastname: Yanagisawa
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ohtake
authors.forename: Satoko
authors.initials: S
authors.lastname: Ogawa
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shibuya
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Gotoh
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
mesh_terms: 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
chemical_list: 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