Tumor necrosis factor alpha (TNFalpha) stimulates Map4k4 expression through TNFalpha receptor 1 signaling to c-Jun and activating transcription factor 2
AuthorsTesz, Gregory J.
Guilherme, Adilson L.
Guntur, Kalyani V. P.
Hubbard, Andrea C.
Czech, Michael P.
UMass Chan AffiliationsProgram in Molecular Medicine
Graduate School of Biomedical Sciences
Document TypeJournal Article
Keywords3T3 Cells; Activating Transcription Factor 2; Adipocytes; Animals; Glucose Transporter Type 4; Inflammation; Insulin Resistance; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Macrophages; Mice; Mitogen-Activated Protein Kinases; PPAR gamma; Phosphorylation; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-jun; RNA, Small Interfering; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; *Signal Transduction; Tumor Necrosis Factor-alpha; *Up-Regulation
Medicine and Health Sciences
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AbstractTumor necrosis factor alpha (TNFalpha) is a cytokine secreted by macrophages and adipocytes that contributes to the low grade inflammation and insulin resistance observed in obesity. TNFalpha signaling decreases peroxisome proliferator-activated receptor gamma and glucose transporter isoform 4 (GLUT4) expression in adipocytes, impairing insulin action, and this is mediated in part by the yeast Ste20 protein kinase ortholog Map4k4. Here we show that Map4k4 expression is selectively up-regulated by TNFalpha, whereas the expression of the protein kinases JNK1/2, ERK1/2, p38 stress-activated protein kinase, and mitogen-activated protein kinase kinases 4/7 shows little or no response. Furthermore, the cytokines interleukin 1beta (IL-1beta) and IL-6 as well as lipopolysaccharide fail to increase Map4k4 mRNA levels in cultured adipocytes under conditions where TNFalpha elicits a 3-fold effect. Using agonistic and antagonistic antibodies and small interfering RNA (siRNA) against TNFalpha receptor 1 (TNFR1) and TNFalpha receptor 2 (TNFR2), we show that TNFR1, but not TNFR2, mediates the increase in Map4k4 expression. TNFR1, but not TNFR2, also mediates a potent effect of TNFalpha on the phosphorylation of JNK1/2 and p38 stress-activated protein kinase and their downstream transcription factor substrates c-Jun and activating transcription factor 2 (ATF2). siRNA-based depletion of c-Jun and ATF2 attenuated TNFalpha action on Map4k4 mRNA expression. Consistent with this concept, the phosphorylation of ATF2 along with the expression and phosphorylation of c-Jun by TNFalpha signaling was more robust and prolonged compared with that of IL-1beta, which failed to modulate Map4k4. These data reveal that TNFalpha selectively stimulates the expression of a key component of its own signaling pathway, Map4k4, through a TNFR1-dependent mechanism that targets the transcription factors c-Jun and ATF2.
SourceJ Biol Chem. 2007 Jul 6;282(27):19302-12. Epub 2007 May 11. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/32688
Related ResourcesLink to Article in PubMed
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