title: Tumor necrosis factor alpha (TNFalpha) stimulates Map4k4 expression through TNFalpha receptor 1 signaling to c-Jun and activating transcription factor 2.
abstract: Tumor 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.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tesz
authors.forename: Adilson
authors.initials: A
authors.lastname: Guilherme
authors.forename: Kalyani V P
authors.initials: KV
authors.lastname: Guntur
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Hubbard
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Tang
authors.forename: Anil
authors.initials: A
authors.lastname: Chawla
authors.forename: Michael P
authors.initials: MP
authors.lastname: Czech
mesh_terms: D016475:3T3 Cells; D051698:Activating Transcription Factor 2 / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D007333:Insulin Resistance; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis*; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000819:agonists / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D051698:Activating Transcription Factor 2; D051275:Glucose Transporter Type 4; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; D047495:PPAR gamma; D017346:Protein Serine-Threonine Kinases; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase; C497106:Atf2 protein, mouse; C495693:Slc2a4 protein, mouse