title: Role of transforming growth factor-activated kinase-1 on tumor necrosis factor-α actions in human adipose tissue-derived stromal cells.
abstract: Tumor necrosis factor-α (TNF-α) has multiple effects on proliferation and differentiation of human mesenchymal stem cells. Transforming growth factor-activated kinase-1 (TAK1) mediates the activation of nuclear factor-kappa B (NF-κB), c-Jun N-terminal kinase (JNK), and p38 pathways in response to TNF-α. However, the role of TAK1 in TNF-α-induced effects in human adipose-derived stem cells (hADSCs) and its signaling pathway has not been clearly defined. Therefore, this study was designated to clarify the role of TAK1 in TNF-α-induced actions on proliferation and differentiation of hADSCs and its downstream signaling pathway. Inhibiting TAK1 expression inhibited the TNF-α-induced increase in osteogenic differentiation and basal osteogenic differentiation without affecting the TNF-α-induced effect on proliferation and adipogenic differentiation of hADSCs. A western blot analysis showed that TNF-α treatment induced degradation of IκB, but that TAK1 small interfering RNA (siRNA) transfection did not protect against TNF-α-induced IκB degradation. The transfection of TAK1 siRNA also did not affect TNF-α-induced IκB phosphorylation or ERK1/2 phosphorylation. However, downregulating TAK1 inhibited this TNF-α-induced S536 phosphorylation of the p65 subunit. TNF-α treatment induced p38 phosphorylation, which was inhibited by the transfection of TAK1 siRNA. Adding p38 inhibitor inhibited TNF-α-induced p65 phosphorylation, NF-κB promoter activity, and TNF-α-induced increase in hADSC osteogenic differentiation. These data indicate that TAK1 is involved in the TNF-α-induced activation of p38 kinase, which subsequently phosphorylates the NF-κB p65 subunit, and increases the transactivation potential of p65 and osteogenic differentiation in hADSCs.
authors.affiliation: 1 Department of Physiology, School of Medicine, Pusan National University , Yangsan, Gyeongnam, Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Jung Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Keun Koo
authors.initials: KK
authors.lastname: Shin
authors.forename: Da Sol
authors.initials: DS
authors.lastname: Kim
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Kim
authors.forename: Yong Chan
authors.initials: YC
authors.lastname: Bae
authors.forename: Jin Sup
authors.initials: JS
authors.lastname: Jung
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000328:Adult; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7