Tumor Necrosis Factor α (TNFα) Stimulates Map4k4 Expression through TNFα Receptor 1 Signaling to c-Jun and Activating Transcription Factor 2

• Published in: The Journal of biological chemistry 2007-07, Vol.282 (27), p.19302-19312
• Main Authors: Tesz, Gregory J., Guilherme, Adilson, Guntur, Kalyani V.P., Hubbard, Andrea C., Tang, Xiaoqing, Chawla, Anil, Czech, Michael P.
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M700665200

Tumor necrosis factor α (TNFα) is a cytokine secreted by macrophages and adipocytes that contributes to the low grade inflammation and insulin resistance observed in obesity. TNFα signaling decreases peroxisome proliferator-activated receptor γ 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 TNFα, 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 1β (IL-1β) and IL-6 as well as lipopolysaccharide fail to increase Map4k4 mRNA levels in cultured adipocytes under conditions where TNFα elicits a 3-fold effect. Using agonistic and antagonistic antibodies and small interfering RNA (siRNA) against TNFα receptor 1 (TNFR1) and TNFα 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 TNFα 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 TNFα action on Map4k4 mRNA expression. Consistent with this concept, the phosphorylation of ATF2 along with the expression and phosphorylation of c-Jun by TNFα signaling was more robust and prolonged compared with that of IL-1β, which failed to modulate Map4k4. These data reveal that TNFα 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.