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J. Biol. Chem., Vol. 282, Issue 16, 11629-11638, April 20, 2007

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Post-induction, Stimulus-specific Regulation of Tumor Necrosis Factor mRNA Expression^*

Alla V. Tsytsykova, James V. Falvo, Marc Schmidt-Supprian^¶, Gilles Courtois^||, Dimitris Thanos^**1, and Anne E. Goldfeld²

From the CBR Institute for Biomedical Research and Departments of Medicine, Pediatrics, and ^¶Pathology, Harvard Medical School, Boston, Massachusetts 02115, ^||INSERM, Pavillon Bazin, Hôpital Saint-Louis, 75010 Paris, France, ^**Institute of Molecular Biology and Genetics, Biomedical Sciences Research Center "Alexander Fleming," 16602 Vari, Athens, Greece, and the Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032

The tumor necrosis factor (TNF) gene is activated by multiple extracellular signals in a stimulus- and cell type-specific fashion. Based on the presence of B-like DNA motifs in the region upstream of the TNF gene, some have proposed a direct role for NF-B in lipopolysaccharide (LPS)-induced TNF gene transcription in cells of the monocyte/macrophage lineage. However, we have previously demonstrated a general and critical role for a minimal TNF promoter region bearing only one of the B-like motifs, 3, which is bound by nuclear factor of activated T cell proteins in lymphocytes and fibroblasts in response to multiple stimuli and Ets proteins in LPS-stimulated macrophages. Here, in an effort to resolve these contrasting findings, we used a combination of site-directed mutagenesis of the TNF promoter, quantitative DNase I footprinting, and analysis of endogenous TNF mRNA production in response to multiple stimuli under conditions that inhibit NF-B activation (using the proteasome inhibitor lactacystin and using cells lacking either functional NF-B essential modulator, which is the IB kinase regulatory subunit, or the Nemo gene itself). We find that TNF mRNA production in response to ionophore is NF-B-independent, but inhibition of NF-B activation attenuates virus- and LPS-induced TNF mRNA levels after initial induction. We conclude that induction of TNF gene transcription by virus or LPS does not depend upon NF-B binding to the proximal promoter; rather, a stimulus-specific post-induction mechanism involving NF-B, yet to be characterized, is involved in the maintenance of maximal TNF mRNA levels.

Received for publication, December 13, 2006 , and in revised form, February 1, 2007.

^* This work was supported by National Institutes of Health Grant GM076685 (to A. E. G.). 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.

¹ Present address: Inst. of Molecular Biology, Genetics and Biotechnology, Foundation for Biomedical Research, Academy of Athens, 4 Soranou Efesiou St., 11527 Athens, Greece.

² To whom correspondence should be addressed: CBR Institute for Biomedical Research, 800 Huntington Ave., Boston, MA 02115. Tel.: 617-278-3351; Fax: 617-278-3454; E-mail: goldfeld{at}cbrinstitute.org.

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