scholarly journals Retinoids downregulate both p60 and p80 forms of tumor necrosis factor receptors in human histiocytic lymphoma U-937 cells

Blood ◽  
1995 ◽  
Vol 85 (12) ◽  
pp. 3547-3555 ◽  
Author(s):  
K Totpal ◽  
MM Chaturvedi ◽  
R LaPushin ◽  
BB Aggarwal
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Leukemia Cell Line ◽  
Cell Surface Expression ◽  
Scatchard Analysis ◽  
Dependent Manner ◽  
Tnf Receptor ◽  
Tnf Receptors ◽  
Histiocytic Lymphoma ◽  
Necrosis Factor

Because retinoids are known to modulate the growth and differentiation effects of tumor necrosis factor (TNF), we investigated the effect of all-trans-retinoic acid (RA) on the cell surface expression of TNF receptors in human histiocytic lymphoma U-937 cells. RA decreased the specific binding of 125I-labeled TNF to these cells in a dose- and time-dependent manner. The maximal decrease occurred when cells were treated with 1 mumol/L RA for 24 hours at 37 degrees C. Scatchard analysis of the binding indicated that the decrease by RA was caused by a decrease in receptor number and not by a decrease in affinity. The downmodulation of TNF receptors was also confirmed by covalent receptor-ligand cross-linking studies. Receptor-mediated internalization of the ligand was also found to be decreased on treatment of cells with RA. Northern blot analysis also indicated a decrease in the transcript of the receptor. By using antibodies specific to either the p60 or p80 form of the TNF receptor, we found that both receptors were downregulated by RA. RA treatment also decreased TNF receptors on acute monocytic leukemia cell line THP-1. Other analogues of RA, specifically 9-cis-RA, (E)-4-[2-(5,6,7,8-tetrahydro-2-naphthalenyl)-1-propenyl]-benzoic acid (TTNPB), and 3-methyl-TTNPB, which differ in their specificity towards different RA receptors, were also active in downregulating TNF receptors. 3-Methyl-TTNPB, which is more specific for the RXR form of the RA receptor, was found to be most potent. The downregulation of TNF receptors by RA correlated with the downmodulation of the antiproliferative effects of TNF against U-937 cells. Overall, our results indicate that RA downmodulates both the p60 and p80 form of the TNF receptor on cells of myeloid origin, which correlates with the cellular response.

Evidence that genetic deletion of the TNF receptor p60 or p80 in macrophages modulates RANKL-induced signaling

Blood ◽  
2004 ◽  
Vol 104 (13) ◽  
pp. 4113-4121 ◽  
Author(s):  
Yasunari Takada ◽  
Bharat B. Aggarwal
Keyword(s):  
Tumor Necrosis Factor ◽  
Cross Talk ◽  
Tumor Necrosis ◽  
No Production ◽  
Dependent Manner ◽  
Tnf Receptor ◽  
Wild Type ◽  
Tnf Receptors ◽  
Genetic Deletion ◽  
Necrosis Factor

Abstract In the current report, we investigated the possibility of a cross-talk between receptor activator of NF-κB ligand (RANKL) and tumor necrosis factor α (TNF-α) using macrophage cell lines derived from wild-type mice and from mice with genetic deletion of the type 1 TNF receptor (p60-/-), the type 2 TNF receptor (p80-/-), or both receptors (p60-/-p80-/-). Deletion of TNF receptors sensitized the cells to RANKL-induced NF-κB activation, in order from least to most sensitive of p60-/- less than p80-/- less than p60-/-p80-/-. The effect on nuclear factor-κB (NF-κB) activation correlated with RANKL-induced IκBα kinase activation. Deletion of both TNF receptors also potentiated RANKL-induced c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1 and 2 (ERK1/2), and p38 mitogen-activated protein kinase (MAPK) activations in a dose- and time-dependent manner. Nitric oxide (NO) production and expression of inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2) induced by RANKL was also maximally induced in double knock-out cells. RANKL had no effect on the proliferation of wild-type cells, but deletion of TNF receptors induced growth modulatory effects. We also found that tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), which mediates RANKL signaling, was constitutively bound to RANK in TNF receptor-deleted cells but not in wild-type cells, and this binding was enhanced by RANKL. Overall our results show that RANKL signaling is modulated by the TNF receptors and thus provide evidence of cross-talk between the receptors of 2 cytokines. (Blood. 2004;104: 4113-4121)

scholarly journals A human tumor necrosis factor (TNF) alpha mutant that binds exclusively to the p55 TNF receptor produces toxicity in the baboon.

1994 ◽  
Vol 179 (4) ◽  
pp. 1185-1191 ◽  
Author(s):  
K J Van Zee ◽  
S A Stackpole ◽  
W J Montegut ◽  
M A Rogy ◽  
S E Calvano ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Lethal Dose ◽  
Human Tumor ◽  
Receptor Activation ◽  
Tnf Alpha ◽  
Tnf Receptor ◽  
Tnf Receptors ◽  
Necrosis Factor

A number of recent studies have demonstrated that cellular responses to tumor necrosis factor (TNF) mediated by the p55 and the p75 TNF receptors are distinct. To evaluate the relative in vivo toxicities of wild-type TNF alpha (wtTNF alpha) and a novel p55 TNF selective receptor agonist, healthy, anesthetized baboons (Papio sp.) were infused with a near-lethal dose of either wtTNF alpha or a TNF alpha double mutant (dmTNF alpha) that binds specifically to the p55, but not to the p75, TNF receptor. Both wtTNF alpha and dmTNF alpha produced comparable acute hypotension, tachycardia, increased plasma lactate, and organ dysfunction in Papio. However, administration of wtTNF alpha produced a marked granulocytosis and loss of granulocyte TNF receptors, whereas little if any changes in neutrophil number or cell surface TNF receptor density were seen after dmTNF alpha mutant administration. Infusion of dmTNF alpha resulted in a plasma endogenous TNF alpha response that peaked after 90-120 min. We conclude that selective p55 TNF receptor activation is associated with early hemodynamic changes and the autocrine release of endogenous TNF alpha. Significant systemic toxicity results from p55 TNF receptor activation, but the role of the p75 TNF receptor in systemic TNF toxicity requires further study.

Dexamethasone inhibits IL-1 and TNF activity in human lung fibroblasts without affecting IL-1 or TNF receptors

1994 ◽  
Vol 267 (1) ◽  
pp. L33-L38 ◽  
Author(s):  
M. M. Monick ◽  
T. R. Aksamit ◽  
L. J. Geist ◽  
G. W. Hunninghake
Keyword(s):  
Tumor Necrosis ◽  
Human Lung ◽  
Lung Fibroblasts ◽  
Dependent Manner ◽  
Tnf Receptor ◽  
Tnf Receptors ◽  
Human Lung Fibroblasts ◽  
Specific Receptors ◽  
Dose Dependent ◽  
Necrosis Factor

Interleukin (IL-1) and tumor necrosis factor (TNF) activate human lung fibroblasts through interactions with specific receptors. One effect of this interaction of IL-1 and TNF with fibroblasts is an increased production of the cytokines, IL-6 and IL-8. Dexamethasone blocks the induction of IL-6 and IL-8 by IL-1 or TNF. In these studies, we determined whether dexamethasone interferes with the upregulation of IL-6 and IL-8 by downregulating expression of the IL-1 or TNF receptor genes. Confluent lung fibroblasts were treated with medium alone (control) or medium with dexamethasone (10(-6) M). Dexamethasone did not decrease the binding of IL-1 and TNF to their receptors, nor did it decrease amounts of IL-1 or TNF receptor RNA. Both IL-1 and TNF increased release of IL-6 and IL-8 from the cells in a dose-dependent manner and dexamethasone inhibited this effect. Dexamethasone also inhibited the induction of IL-6 and IL-8 RNA by IL-1 and TNF. The studies show that dexamethasone does not block the effects of IL-1 or TNF on fibroblasts by decreasing expression of IL-1 or TNF receptors.

The Effect of a Metalloproteinase Inhibitor (GI5402) on Tumor Necrosis Factor- (TNF-) and TNF- Receptors During Human Endotoxemia

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2252-2258 ◽  
Author(s):  
Pascale E.P. Dekkers ◽  
Fanny N. Lauw ◽  
Tessa ten Hove ◽  
Anje A. te Velde ◽  
Philip Lumley ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Surface Expression ◽  
Receptor Expression ◽  
Tnf Receptor ◽  
Tnf Receptors ◽  
Proinflammatory Effect ◽  
Necrosis Factor

Tumor necrosis factor- (TNF-) is released from the cell surface by cleavage of pro–TNF- by metalloproteinases (MPs). In cell cultures, inhibition of MPs has been found not only to reduce the release of TNF-, but also to enhance the surface expression of TNF- and TNF- receptors, which might lead to a proinflammatory effect. To determine the effect of MP inhibition during inflammation in humans, 7 healthy subjects were studied after intravenous injection of lipopolysaccharide (LPS; 4 ng/kg) preceded (−20 minutes) by an oral dose of the MP inhibitor GI5402 (100 mg) or matching placebo. GI5402 strongly reduced LPS-induced TNF- release (P < .001), but did not influence the increase in monocyte-bound TNF-. In addition, GI5402 attenuated the rise in plasma-soluble TNF- receptors types I and II after LPS injection (both P < .001), but did not change the LPS-induced decreases in granulocyte and monocyte TNF- receptor expression. These data suggest that MP inhibitors may be useful as a treatment modality in diseases in which excessive production of TNF- is considered to play an important role. Furthermore, unlike in vitro, no evidence has been found in vivo with MP inhibition for a potential proinflammatory effect due to increases in membrane-bound TNF- and TNF- receptor number.

scholarly journals Tumor necrosis factor (TNF)-induced protein phosphorylation in a human rhabdomyosarcoma cell line is mediated by 60-kD TNF receptors (TR60)

Blood ◽  
1994 ◽  
Vol 83 (8) ◽  
pp. 2211-2220 ◽  
Author(s):  
A Mire-Sluis ◽  
A Meager
Keyword(s):  
Tumor Necrosis Factor ◽  
Protein Phosphorylation ◽  
Cell Line ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Tnf Receptors ◽  
Protein Kinase C Inhibitors ◽  
Rhabdomyosarcoma Cell Line ◽  
Rhabdomyosarcoma Cell ◽  
Necrosis Factor

Abstract In the present study, we used a cloned derivative, KYM-1D4, of the human rhabdomyosarcoma cell line, KYM-1, known to express high numbers of the two tumor necrosis factor (TNF) receptors, TR60 and TR80, and to be highly sensitive to TNF alpha-mediated cytotoxicity/antiproliferation, to investigate the role of TR60 and TR80 in protein phosphorylation. Using permeabilized KYM-1D4 cells, it was found that TNF alpha strongly induced phosphorylation of proteins of molecular weight 80, 65, 58, 42, and 30 kD. Addition of a monoclonal antibody (MoAb) against TR60 was shown to induce cytotoxicity/antiproliferation in KYM-1D4 cells and the same pattern of protein phosphorylation as TNF alpha, whereas addition of an MoAb against TR80 was both noncytotoxic and ineffective in inducing protein phosphorylation. In contrast, in a highly TNF alpha-resistant KYM-1- derived cell line, 37B8R, no protein phosphorylation was induced with either TNF alpha or the agonistic anti-TR60 MoAb. However, when 37B8R was allowed to revert to partial TNF sensitivity by culture in the absence of TNF alpha, the resultant cell line, 37B8S, was found to regain inducibility of protein phosphorylation by TNF alpha. These results indicate that expression of functional TR60 in KYM-1-related cell lines is principally involved in TNF-mediated cytotoxicity/antiproliferation and is necessary for the induction of protein phosphorylation. Nevertheless, the latter, although apparently strongly associated with cytotoxicity, was probably involved in protective mechanisms because protein kinase C inhibitors that inhibited TNF alpha and anti-TR60-induced phosphorylation increased the cytotoxic/antiproliferative response to these mediators.

scholarly journals The α and β Subunits of IκB Kinase (IKK) Mediate TRAF2-Dependent IKK Recruitment to Tumor Necrosis Factor (TNF) Receptor 1 in Response to TNF

2001 ◽  
Vol 21 (12) ◽  
pp. 3986-3994 ◽  
Author(s):  
Anne Devin ◽  
Yong Lin ◽  
Shoji Yamaoka ◽  
Zhiwei Li ◽  
Michael Karin ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Leucine Zipper ◽  
Nuclear Translocation ◽  
Ring Finger ◽  
Tnf Receptor ◽  
Death Domain ◽  
Iκb Kinase ◽  
Cytokine Tumor Necrosis Factor ◽  
Necrosis Factor

ABSTRACT The activation of IκB kinase (IKK) is a key step in the nuclear translocation of the transcription factor NF-κB. IKK is a complex composed of three subunits: IKKα, IKKβ, and IKKγ (also called NEMO). In response to the proinflammatory cytokine tumor necrosis factor (TNF), IKK is activated after being recruited to the TNF receptor 1 (TNF-R1) complex via TNF receptor-associated factor 2 (TRAF2). We found that the IKKα and IKKβ catalytic subunits are required for IKK-TRAF2 interaction. This interaction occurs through the leucine zipper motif common to IKKα, IKKβ, and the RING finger domain of TRAF2, and either IKKα or IKKβ alone is sufficient for the recruitment of IKK to TNF-R1. Importantly, IKKγ is not essential for TNF-induced IKK recruitment to TNF-R1, as this occurs efficiently in IKKγ-deficient cells. Using TRAF2−/− cells, we demonstrated that the TNF-induced interaction between IKKγ and the death domain kinase RIP is TRAF2 dependent and that one possible function of this interaction is to stabilize the IKK complex when it interacts with TRAF2.

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