title: TNF-like weak inducer of apoptosis (TWEAK) activates proinflammatory signaling pathways and gene expression through the activation of TGF-beta-activated kinase 1.
abstract: 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-beta-activated kinase 1) is involved in TWEAK-induced activation of NF-kappaB 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-kappaB 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 IkappaB kinase and the phosphorylation and degradation of IkappaBalpha 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-kappaB 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-kappaB 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.
authors.affiliation: Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Kumar
authors.forename: Denys Y
authors.initials: DY
authors.lastname: Makonchuk
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Ashwani
authors.initials: A
authors.lastname: Mittal
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000276:immunology*; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology*; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000276:immunology*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000276:immunology / Q000378:metabolism; D032446:Myoblasts / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000276:immunology / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000074049:Cytokine TWEAK; D020930:MAP Kinase Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D016328:NF-kappa B; D051057:Proto-Oncogene Proteins c-akt; D018808:Transcription Factor AP-1; D048069:Tumor Necrosis Factors; D000099151:MAP Kinase Kinase Kinase 7; C491645:Tnfsf12 protein, mouse