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J. Biol. Chem., Vol. 282, Issue 27, 19302-19312, July 6, 2007

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

From the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605

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

Received for publication, January 23, 2007 , and in revised form, May 9, 2007.

^* This work was supported by National Institutes of Health Grant DK30898 (to M. P. C.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation St., Suite 100, Worcester, MA 01605. Tel.: 508-856-2254; Fax: 508-856-1617; E-mail: Michael.Czech{at}umassmed.edu.

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