期刊
CELLULAR SIGNALLING
卷 19, 期 3, 页码 646-657出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2006.08.017
关键词
TAB1; TAK1; translocation; MAPK; NF kappa B; cytokines
类别
Biochemical evidence indicates that TGF-beta-activated kinase 1 (TAK1), a key modulator of the inflammatory response, exists in a complex with various adaptor proteins including the TAK1 binding protein 1 (TAB1). However, the physiological importance of TAB1 in TAK1 activation, and in the subsequent induction of proinflammatory mediators, remains unclear. In this study, a critical role for TAK1 in IL-1 alpha or TNF alpha stimulated MAPK and NF kappa B activation was confirmed by inhibition of the nuclear accumulation of NF kappa B p65 and phosphorylated forms of c-Jun and p38 following siRNA mediated TAK1 silencing. These effects were associated with significant reductions in IL-1a stimulated levels of secreted IL-6, IL-8, MCP-1 and GM-CSF. In contrast, IL-1 alpha or TNF alpha dependent cellular redistribution of NF kappa B p65 and phosphorylated c-Jun and p38 was not affected by 80% siRNA mediated knockdown of TAB I protein levels. Interestingly, IL-6, IL-8 and GM-CSF release from TAB I siRNA transfected cells was significantly reduced following IL-1 alpha treatment, but was unchanged after TNFa stimulation, suggesting differential roles for TAB1 in IL-1 alpha and TNF alpha signalling pathways. These findings may imply an as yet unidentified role for TAB I in the inflammatory response, which is independent of the activation of classical TAK1 associated signalling cascades. (c) 2006 Elsevier Inc. All rights reserved.
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