Genome Wide Characterization & Phylogenetic Analysis of TNF Genes in Homo Sapiens

The treatment of human HL-60 promyelocytic leukemia cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with induction of tumor necrosis factor (TNF) transcript. The study reported here has examined TPA-induced signaling mechanisms responsible for the regulation of TNF gene expression in these cells. Run-on assays demonstrated that TPA increases TNF mRNA levels by transcriptional activation of this gene. The induction of TNF transcripts by TPA was inhibited by the isoquinolinesulfonamide derivative H7 but not by HA1004, suggesting that this effect of TPA is mediated by activation of protein kinase C. TPA treatment also resulted in increased arachidonic acid release. Moreover, inhibitors of phospholipase A2 blocked both the increase in arachidonic acid release and the induction of TNF transcripts. These findings suggest that TPA induces TNF gene expression through the formation of arachidonic acid metabolites. Although indomethacin had no detectable effect on this induction of TNF transcripts, ketoconazole, an inhibitor of 5-lipoxygenase, blocked TPA-induced increases in TNF mRNA levels. Moreover, TNF mRNA levels were increased by the 5-lipoxygenase metabolite leukotriene B4. In contrast, the cyclooxygenase metabolite prostaglandin E2 inhibited the induction of TNF transcripts by TPA. Taken together, these results suggest that TPA induces TNF gene expression through the arachidonic acid cascade and that the level of TNF transcripts is regulated by metabolites of the pathway, leukotriene B4 and prostaglandin E2.

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Tumor Necrosis Factor Alpha Inhibits Type I Collagen Synthesis through Repressive CCAAT/Enhancer-Binding Proteins

Molecular and Cellular Biology ◽

10.1128/mcb.20.3.912-918.2000 ◽

2000 ◽

Vol 20 (3) ◽

pp. 912-918 ◽

Cited By ~ 115

Author(s):

Patricia Greenwel ◽

Shizuko Tanaka ◽

Dmitri Penkov ◽

Wen Zhang ◽

Michelle Olive ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Type I Collagen ◽

Type I ◽

Necrosis Factor Alpha ◽

Gene Coding ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor ◽

Stimulation Of

ABSTRACT Extracellular matrix (ECM) formation and remodeling are critical processes for proper morphogenesis, organogenesis, and tissue repair. The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) inhibits ECM accumulation by stimulating the expression of matrix proteolytic enzymes and by downregulating the deposition of structural macromolecules such as type I collagen. Stimulation of ECM degradation has been linked to prolonged activation of jun gene expression by the cytokine. Here we demonstrate that TNF-α inhibits transcription of the gene coding for the α2 chain of type I collagen [α2(I) collagen] in cultured fibroblasts by stimulating the synthesis and binding of repressive CCAAT/enhancer proteins (C/EBPs) to a previously identified TNF-α-responsive element. This conclusion was based on the concomitant identification of C/EBPβ and C/EBPδ as TNF-α-induced factors by biochemical purification and expression library screening. It was further supported by the ability of the C/EBP-specific dominant-negative (DN) protein to block TNF-α inhibition of α2(I) collagen but not TNF-α stimulation of the MMP-13 protease. The DN protein also blocked TNF-α downregulation of the gene coding for the α1 chain of type I collagen. The study therefore implicates repressive C/EBPs in the TNF-α-induced signaling pathway that controls ECM formation and remodeling.

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Vpr Enhances Tumor Necrosis Factor Production by HIV-1-Infected T Cells

Journal of Virology ◽

10.1128/jvi.02098-15 ◽

2015 ◽

Vol 89 (23) ◽

pp. 12118-12130 ◽

Cited By ~ 16

Author(s):

Ferdinand Roesch ◽

Léa Richard ◽

Réjane Rua ◽

Françoise Porrot ◽

Nicoletta Casartelli ◽

...

Keyword(s):

Immune Responses ◽

Proinflammatory Cytokine ◽

Tumor Necrosis ◽

Cellular Proteins ◽

Accessory Protein ◽

Infected Cells ◽

Hiv 1 ◽

Necrosis Factor ◽

Stimulation Of

ABSTRACTThe HIV-1 accessory protein Vpr displays different activities potentially impacting viral replication, including the arrest of the cell cycle in the G2phase and the stimulation of apoptosis and DNA damage response pathways. Vpr also modulates cytokine production by infected cells, but this property remains partly characterized. Here, we investigated the effect of Vpr on the production of the proinflammatory cytokine tumor necrosis factor (TNF). We report that Vpr significantly increases TNF secretion by infected lymphocytes.De novoproduction of Vpr is required for this effect. Vpr mutants known to be defective for G2cell cycle arrest induce lower levels of TNF secretion, suggesting a link between these two functions. Silencing experiments and the use of chemical inhibitors further implicated the cellular proteins DDB1 and TAK1 in this activity of Vpr. TNF secreted by HIV-1-infected cells triggers NF-κB activity in bystander cells and allows viral reactivation in a model of latently infected cells. Thus, the stimulation of the proinflammatory pathway by Vpr may impact HIV-1 replicationin vivo.IMPORTANCEThe role of the HIV-1 accessory protein Vpr remains only partially characterized. This protein is important for viral pathogenesis in infected individuals but is dispensable for viral replication in most cell culture systems. Some of the functions described for Vpr remain controversial. In particular, it remains unclear whether Vpr promotes or instead prevents proinflammatory and antiviral immune responses. In this report, we show that Vpr promotes the release of TNF, a proinflammatory cytokine associated with rapid disease progression. Using Vpr mutants or inhibiting selected cellular genes, we show that the cellular proteins DDB1 and TAK1 are involved in the release of TNF by HIV-infected cells. This report provides novel insights into how Vpr manipulates TNF production and helps clarify the role of Vpr in innate immune responses and inflammation.

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Role of arachidonic acid metabolism in transcriptional induction of tumor necrosis factor gene expression by phorbol ester

Molecular and Cellular Biology ◽

10.1128/mcb.9.1.252-258.1989 ◽

1989 ◽

Vol 9 (1) ◽

pp. 252-258

Author(s):

J Horiguchi ◽

D Spriggs ◽

K Imamura ◽

R Stone ◽

R Luebbers ◽

...

Keyword(s):

Gene Expression ◽

Arachidonic Acid ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Leukotriene B4 ◽

Mrna Levels ◽

Arachidonic Acid Release ◽

Acid Release ◽

Tnf Gene ◽

Necrosis Factor

The treatment of human HL-60 promyelocytic leukemia cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with induction of tumor necrosis factor (TNF) transcript. The study reported here has examined TPA-induced signaling mechanisms responsible for the regulation of TNF gene expression in these cells. Run-on assays demonstrated that TPA increases TNF mRNA levels by transcriptional activation of this gene. The induction of TNF transcripts by TPA was inhibited by the isoquinolinesulfonamide derivative H7 but not by HA1004, suggesting that this effect of TPA is mediated by activation of protein kinase C. TPA treatment also resulted in increased arachidonic acid release. Moreover, inhibitors of phospholipase A2 blocked both the increase in arachidonic acid release and the induction of TNF transcripts. These findings suggest that TPA induces TNF gene expression through the formation of arachidonic acid metabolites. Although indomethacin had no detectable effect on this induction of TNF transcripts, ketoconazole, an inhibitor of 5-lipoxygenase, blocked TPA-induced increases in TNF mRNA levels. Moreover, TNF mRNA levels were increased by the 5-lipoxygenase metabolite leukotriene B4. In contrast, the cyclooxygenase metabolite prostaglandin E2 inhibited the induction of TNF transcripts by TPA. Taken together, these results suggest that TPA induces TNF gene expression through the arachidonic acid cascade and that the level of TNF transcripts is regulated by metabolites of the pathway, leukotriene B4 and prostaglandin E2.

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