A systems-biology model of the tumor necrosis factor (TNF) interactions with TNF receptor 1 and 2

2020 ◽  
Author(s):  
Juan Pablo Prada ◽  
Gaby Wangorsch ◽  
Kirstin Kucka ◽  
Isabell Lang ◽  
Thomas Dandekar ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Large Range ◽  
Supplementary Information ◽  
Tnf Receptor ◽  
Tnf Receptors ◽  
Rule Based ◽  
Soluble Ligand ◽  
Receptor Clusters ◽  
Clustering Behavior ◽  
Necrosis Factor

Abstract Motivation Clustering enables TNF receptors to stimulate intracellular signaling. The differential soluble ligand-induced clustering behavior of TNF receptor 1 (TNFR1) and TNFR2 was modeled. A structured, rule-based model implemented ligand-independent pre-ligand binding assembly domain (PLAD)-mediated homotypic low affinity interactions of unliganded and liganded TNF receptors. Results Soluble TNF initiates TNFR1 signaling but not TNFR2 signaling despite receptor binding unless it is secondarily oligomerized. We consider high affinity binding of TNF to signaling-incompetent pre-assembled dimeric TNFR1 and TNFR2 molecules and secondary clustering of liganded dimers to signaling competent ligand–receptor clusters. Published receptor numbers, affinities and measured different activities of clustered receptors validated model simulations for a large range of receptor and ligand concentrations. Different PLAD–PLAD affinities and different activities of receptor clusters explain the observed differences in the TNF receptor stimulating activities of soluble TNF. Availability and implementation All scripts and data are in manuscript and supplement at Bioinformatics online. Supplementary information Supplementary data are available at Bioinformatics online.

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.

scholarly journals Receptors for tumor necrosis factor on neoplastic B cells from chronic lymphocytic leukemia are expressed in vitro but not in vivo

Blood ◽  
1990 ◽  
Vol 76 (8) ◽  
pp. 1607-1613 ◽  
Author(s):  
W Digel ◽  
W Schoniger ◽  
M Stefanic ◽  
H Janssen ◽  
C Buck ◽  
...  
Keyword(s):  
B Cells ◽  
Tumor Necrosis ◽  
Lymphocytic Leukemia ◽  
Receptor Expression ◽  
Tnf Alpha ◽  
Tnf Receptor ◽  
Tnf Receptors ◽  
Necrosis Factor

Abstract Recombinant tumor necrosis factor-alpha (TNF-alpha) is a cytokine that induces proliferation of neoplastic B cells from patients with chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms involved in regulating TNF responsiveness, we have examined TNF receptor expression on neoplastic B-CLL cells. We have demonstrated that freshly isolated neoplastic B cells from patients with CLL did not express TNF receptors. After 1 day of incubation in culture medium, TNF receptors were detectable in the range of 540 to 1,500/cell. Kinetic experiments revealed that receptor expression was half-maximal after 3 hours of culturing and required de novo protein synthesis. The Scatchard plots of TNF-alpha binding indicated a single set of high- affinity TNF receptors with a dissociation constant of 70 pmol/L. TNF receptor expression in vitro was found in all examined cases. All cytokines tested, with the exception of IL-2, did not influence the expression of TNF receptors. The TNF receptor expression is enhanced in B-CLL cells cultured in the presence of interleukin-2 when compared with the receptor expression of cells cultured in medium alone. Our data suggest that neoplastic B-CLL cells in patients with stable disease do not express TNF receptors in vivo and that an unknown mechanism suppressing TNF receptor expression in vivo may play a role in growth regulation of neoplastic B cells.

LPS induces apoptosis in macrophages mostly through the autocrine production of TNF-α

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3823-3831 ◽  
Author(s):  
Jordi Xaus ◽  
Mònica Comalada ◽  
Annabel F. Valledor ◽  
Jorge Lloberas ◽  
Francisco López-Soriano ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Endotoxic Shock ◽  
Late Phase ◽  
No Synthase ◽  
Tnf Receptor ◽  
Tnf Receptors ◽  
Tnf Α ◽  
Early Apoptosis ◽  
Induced Apoptosis ◽  
Necrosis Factor

The deleterious effects of lipopolysaccharide (LPS) during endotoxic shock are associated with the secretion of tumor necrosis factor (TNF) and the production of nitric oxide (NO), both predominantly released by tissue macrophages. We analyzed the mechanism by which LPS induces apoptosis in bone marrow-derived macrophages (BMDM). LPS-induced apoptosis reached a plateau at about 6 hours of stimulation, whereas the production of NO by the inducible NO-synthase (iNOS) required between 12 and 24 hours. Furthermore, LPS-induced early apoptosis was only moderately reduced in the presence of an inhibitor of iNOS or when using macrophages from iNOS -/-mice. In contrast, early apoptosis was paralleled by the rapid secretion of TNF and was almost absent in macrophages from mice deficient for one (p55) or both (p55 and p75) TNF-receptors. During the late phase of apoptosis (12-24 hours) NO significantly contributed to the death of macrophages even in the absence of TNF-receptor signaling. NO-mediated cell death, but not apoptosis induced by TNF, correlated with the induction of p53 and Bax genes. Thus, LPS-induced apoptosis results from 2 independent mechanisms: first and predominantly, through the autocrine secretion of TNF- (early apoptotic events), and second, through the production of NO (late phase of apoptosis).

scholarly journals Interleukin-1 alpha upregulates tumor necrosis factor receptors expressed by a human bone marrow stromal cell strain: implications for cytokine redundancy and synergy

Blood ◽  
1995 ◽  
Vol 86 (9) ◽  
pp. 3364-3372 ◽  
Author(s):  
J Caldwell ◽  
SG Emerson
Keyword(s):  
Bone Marrow Stromal Cell ◽  
Interleukin 1 ◽  
Tnf Alpha ◽  
Tnf Receptor ◽  
Tnf Receptors ◽  
Gm Csf ◽  
Synergistic Induction ◽  
Stimulating Factor ◽  
Necrosis Factor ◽  
Csf Production

To explore the biochemical and physiologic basis of the overlapping effects of interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor alpha (TNF-alpha) on myeloid cytokine production, we have studied the dynamics of granulocyte colony-stimulating factor (G-CSF) and granulocyte-monocyte colony-stimulating factor (GM-CSF) production as well as IL-1 receptor and TNF receptor expression in a clonally derived bone marrow stromal cell strain (CDCL). IL-1 alpha and TNF alpha act in a synergistic manner to stimulate G-CSF and GM-CSF production by CDCL, resulting in an increase in CSF secretion that is 250-fold greater than that observed with either cytokine alone. This synergism in protein secretion is paralleled by synergistic increases the steady-state level of GM- and G-CSF mRNA, with supra-additive levels achieved by 24 hours. Coincident with this synergistic induction of myeloid CSFs, treatment of CDCL cells with IL-1 alpha induces a 300% increase in the expression of TNF receptors. IL-1 alpha induction of TNF receptors reaches a peak after 6 hours and gradually returns to baseline level by 24 hours. IL-1 alpha does not affect TNF receptor ligand binding affinity. A kinetic study comparing IL-1/TNF synergistic induction of growth factor secretion with IL-1 alpha induction of TNF receptors shows that these events occur in parallel. In contrast with the induction of TNF receptors by IL-1 alpha, treatment with TNF alpha has no effect on either the number of IL-1 receptors expressed by CDCL cells or IL-1 receptor ligand binding affinity. Brief treatment of IL-1 alpha/TNF alpha-stimulated CDCL cells with cycloheximide before receptor induction reduces the synergistic increase in growth factor mRNA by 40% to 60% compared with cells not treated with CHX. Taken together, these results raise the possibility that IL-1 alpha cross-induction of TNF receptors may contribute to the biochemical mechanisms underlying the synergistic stimulation of G-CSF and GM-CSF production by IL-1 alpha and TNF alpha.

scholarly journals Receptors for tumor necrosis factor on neoplastic B cells from chronic lymphocytic leukemia are expressed in vitro but not in vivo

Blood ◽  
1990 ◽  
Vol 76 (8) ◽  
pp. 1607-1613
Author(s):  
W Digel ◽  
W Schoniger ◽  
M Stefanic ◽  
H Janssen ◽  
C Buck ◽  
...  
Keyword(s):  
B Cells ◽  
Tumor Necrosis ◽  
Lymphocytic Leukemia ◽  
Receptor Expression ◽  
Tnf Alpha ◽  
Tnf Receptor ◽  
Tnf Receptors ◽  
Necrosis Factor

Recombinant tumor necrosis factor-alpha (TNF-alpha) is a cytokine that induces proliferation of neoplastic B cells from patients with chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms involved in regulating TNF responsiveness, we have examined TNF receptor expression on neoplastic B-CLL cells. We have demonstrated that freshly isolated neoplastic B cells from patients with CLL did not express TNF receptors. After 1 day of incubation in culture medium, TNF receptors were detectable in the range of 540 to 1,500/cell. Kinetic experiments revealed that receptor expression was half-maximal after 3 hours of culturing and required de novo protein synthesis. The Scatchard plots of TNF-alpha binding indicated a single set of high- affinity TNF receptors with a dissociation constant of 70 pmol/L. TNF receptor expression in vitro was found in all examined cases. All cytokines tested, with the exception of IL-2, did not influence the expression of TNF receptors. The TNF receptor expression is enhanced in B-CLL cells cultured in the presence of interleukin-2 when compared with the receptor expression of cells cultured in medium alone. Our data suggest that neoplastic B-CLL cells in patients with stable disease do not express TNF receptors in vivo and that an unknown mechanism suppressing TNF receptor expression in vivo may play a role in growth regulation of neoplastic B cells.

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.

LPS induces apoptosis in macrophages mostly through the autocrine production of TNF-α

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3823-3831 ◽  
Author(s):  
Jordi Xaus ◽  
Mònica Comalada ◽  
Annabel F. Valledor ◽  
Jorge Lloberas ◽  
Francisco López-Soriano ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Endotoxic Shock ◽  
Late Phase ◽  
No Synthase ◽  
Tnf Receptor ◽  
Tnf Receptors ◽  
Tnf Α ◽  
Early Apoptosis ◽  
Induced Apoptosis ◽  
Necrosis Factor

Abstract The deleterious effects of lipopolysaccharide (LPS) during endotoxic shock are associated with the secretion of tumor necrosis factor (TNF) and the production of nitric oxide (NO), both predominantly released by tissue macrophages. We analyzed the mechanism by which LPS induces apoptosis in bone marrow-derived macrophages (BMDM). LPS-induced apoptosis reached a plateau at about 6 hours of stimulation, whereas the production of NO by the inducible NO-synthase (iNOS) required between 12 and 24 hours. Furthermore, LPS-induced early apoptosis was only moderately reduced in the presence of an inhibitor of iNOS or when using macrophages from iNOS -/-mice. In contrast, early apoptosis was paralleled by the rapid secretion of TNF and was almost absent in macrophages from mice deficient for one (p55) or both (p55 and p75) TNF-receptors. During the late phase of apoptosis (12-24 hours) NO significantly contributed to the death of macrophages even in the absence of TNF-receptor signaling. NO-mediated cell death, but not apoptosis induced by TNF, correlated with the induction of p53 and Bax genes. Thus, LPS-induced apoptosis results from 2 independent mechanisms: first and predominantly, through the autocrine secretion of TNF- (early apoptotic events), and second, through the production of NO (late phase of apoptosis).

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