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Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202
TWEAK, TNF-like weak inducer of apoptosis, is a relatively recently identified proinflammatory cytokine that functions through binding to Fn14 receptor in target cells. Although TWEAK has been shown to modulate several biological responses, the TWEAK-induced signaling pathways remain poorly understood. In this study, we tested the hypothesis that TAK1 (TGF-β-activated kinase 1) is involved in TWEAK-induced activation of NF-
B and MAPK and expression of proinflammatory protein. TWEAK increased the phosphorylation and kinase activity of TAK1 in cultured myoblast and fibroblast cells. The activation of NF-B was significantly inhibited in TAK1-deficient (TAK1–/–) mouse embryonic fibroblasts (MEF) compared with wild-type MEF. Deficiency of TAK1 also inhibited the TWEAK-induced activation of IB kinase and the phosphorylation and degradation of IB
protein. However, there was no difference in the levels of p100 protein in TWEAK-treated wild-type and TAK1–/– MEF. Furthermore, TWEAK-induced transcriptional activation of NF-B was significantly reduced in TAK1–/– MEF and in C2C12 myoblasts transfected with a dominant-negative TAK1 or TAK1 short interfering RNA. TAK1 was also required for the activation of AP-1 in response to TWEAK. Activation of JNK1 and p38 MAPK, but not ERK1/2 or Akt kinase, was significantly inhibited in TAK1–/– MEF compared with wild-type MEF upon treatment with TWEAK. TWEAK-induced expression of proinflammatory genes such as MMP-9, CCL-2, and VCAM-1 was also reduced in TAK1–/– MEF compared with wild-type MEF. Furthermore, the activation of NF-B and the expression of MMP-9 in response to TWEAK involved the upstream activation of Akt kinase. Collectively, our study demonstrates that TAK1 and Akt are the important components of TWEAK-induced proinflammatory signaling and gene expression.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a National Institutes of Health Grant R01 AG129623 (to A.K.).
2 Address correspondence and reprint requests to Dr. Ashok Kumar, Associate Professor, Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, 500 South Preston Street, Louisville, KY 40202. E-mail address: ashok.kumar{at}louisville.edu
3 Abbreviations used in this paper: TNFSF, TNF super family; DN, dominant negative; HA, hemagglutinin; IKK, IB kinase; MEF, mouse embryonic fibroblast; MKK, MAPK kinase; MMP, matrix metalloprotease; NIK, NF-B-induced kinase; SEAP, secreted alkaline phosphatase; siRNA, short interfering RNA; TAK, TGF-β-activated kinase; TAB, TAK1-binding protein; TRAF, TNFR-associated factor; TWEAK, TNF-related weak inducer of apoptosis.
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  S. P. Fortin, M. J. Ennis, B. A. Savitch, D. Carpentieri, W. S. McDonough, J. A. Winkles, J. C. Loftus, C. Kingsley, G. Hostetter, and N. L. Tran Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Stimulation of Glioma Cell Survival Is Dependent on Akt2 Function Mol. Cancer Res., November 1, 2009; 7(11): 1871 - 1881. [Abstract] [Full Text] [PDF]
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