scholarly journals Receptor Specificity Engineering of TNF Superfamily Ligands

Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 181
Author(s):  
Fengzhi Suo ◽  
Xinyu Zhou ◽  
Rita Setroikromo ◽  
Wim J. Quax
Keyword(s):  
Research Strategy ◽  
Receptor Ligands ◽  
Receptor Specificity ◽  
Tnf Superfamily ◽  
Multiple Receptors ◽  
Specific Receptors ◽  
Necrosis Factor

The tumor necrosis factor (TNF) ligand family has nine ligands that show promiscuity in binding multiple receptors. As different receptors transduce into diverse pathways, the study on the functional role of natural ligands is very complex. In this review, we discuss the TNF ligands engineering for receptor specificity and summarize the performance of the ligand variants in vivo and in vitro. Those variants have an increased binding affinity to specific receptors to enhance the cell signal conduction and have reduced side effects due to a lowered binding to untargeted receptors. Refining receptor specificity is a promising research strategy for improving the application of multi-receptor ligands. Further, the settled variants also provide experimental guidance for engineering receptor specificity on other proteins with multiple receptors.

scholarly journals Accelerated Neutrophil Apoptosis in Mice Lacking A1-a, a Subtype of the bcl-2–related A1 Gene

1998 ◽  
Vol 188 (11) ◽  
pp. 1985-1992 ◽  
Author(s):  
Azumi Hamasaki ◽  
Fujiro Sendo ◽  
Keiko Nakayama ◽  
Noriko Ishida ◽  
Izumi Negishi ◽  
...  
Keyword(s):  
Neutrophil Apoptosis ◽  
Spontaneous Apoptosis ◽  
Wild Type ◽  
Apoptosis Inhibition ◽  
Blood Neutrophils ◽  
Factor Α ◽  
Necrosis Factor

To elucidate the role of A1, a new member of the Bcl-2 family of apoptosis regulators active in hematopoietic cell apoptosis, we established mice lacking A1-a, a subtype of the A1 gene in mice (A1-a−/− mice). Spontaneous apoptosis of peripheral blood neutrophils of A1-a−/− mice was enhanced compared with that of either wild-type mice or heterozygous mutants (A1-a+/− mice). Neutrophil apoptosis inhibition induced by lipopolysaccharide treatment in vitro or transendothelial migration in vivo observed in wild-type mice was abolished in both A1-a−/− and A1-a+/− animals. On the other hand, the extent of tumor necrosis factor α–induced acceleration of neutrophil apoptosis did not differ among A1-a−/−, A1-a+/−, and wild-type mice. The descending order of A1 mRNA expression was wild-type, A1-a+/−, and A1-a−/−. Taken together, these results suggest that A1 is involved in inhibition of certain types of neutrophil apoptosis.

scholarly journals DR5 Knockout Mice Are Compromised in Radiation-Induced Apoptosis

2005 ◽  
Vol 25 (5) ◽  
pp. 2000-2013 ◽  
Author(s):  
Niklas Finnberg ◽  
Joshua J. Gruber ◽  
Peiwen Fei ◽  
Dorothea Rudolph ◽  
Anka Bric ◽  
...  
Keyword(s):  
Cell Death ◽  
Null Mouse ◽  
Organ Specific ◽  
Radiation Induced ◽  
Induced Apoptosis ◽  
The Brain ◽  
Necrosis Factor

ABSTRACT DR5 (also called TRAIL receptor 2 and KILLER) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (also called TRAIL and Apo2 ligand). DR5 is a transcriptional target of p53, and its overexpression induces cell death in vitro. However, the in vivo biology of DR5 has remained largely unexplored. To better understand the role of DR5 in development and in adult tissues, we have created a knockout mouse lacking DR5. This mouse is viable and develops normally with the exception of having an enlarged thymus. We show that DR5 is not expressed in developing embryos but is present in the decidua and chorion early in development. DR5-null mouse embryo fibroblasts expressing E1A are resistant to treatment with TRAIL, suggesting that DR5 may be the primary proapoptotic receptor for TRAIL in the mouse. When exposed to ionizing radiation, DR5-null tissues exhibit reduced amounts of apoptosis compared to wild-type thymus, spleen, Peyer's patches, and the white matter of the brain. In the ileum, colon, and stomach, DR5 deficiency was associated with a subtle phenotype of radiation-induced cell death. These results indicate that DR5 has a limited role during embryogenesis and early stages of development but plays an organ-specific role in the response to DNA-damaging stimuli.

scholarly journals Autonomous TNF is critical for in vivo monocyte survival in steady state and inflammation

2017 ◽  
Vol 214 (4) ◽  
pp. 905-917 ◽  
Author(s):  
Yochai Wolf ◽  
Anat Shemer ◽  
Michal Polonsky ◽  
Mor Gross ◽  
Alexander Mildner ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mononuclear Phagocytes ◽  
Autoimmune Encephalomyelitis ◽  
Wild Type Counterpart ◽  
And Function ◽  
Necrosis Factor ◽  
Experimental Autoimmune

Monocytes are circulating mononuclear phagocytes, poised to extravasate to sites of inflammation and differentiate into monocyte-derived macrophages and dendritic cells. Tumor necrosis factor (TNF) and its receptors are up-regulated during monopoiesis and expressed by circulating monocytes, as well as effector monocytes infiltrating certain sites of inflammation, such as the spinal cord, during experimental autoimmune encephalomyelitis (EAE). In this study, using competitive in vitro and in vivo assays, we show that monocytes deficient for TNF or TNF receptors are outcompeted by their wild-type counterpart. Moreover, monocyte-autonomous TNF is critical for the function of these cells, as TNF ablation in monocytes/macrophages, but not in microglia, delayed the onset of EAE in challenged animals and was associated with reduced acute spinal cord infiltration of Ly6Chi effector monocytes. Collectively, our data reveal a previously unappreciated critical cell-autonomous role of TNF on monocytes for their survival, maintenance, and function.

scholarly journals Role of interleukin-1 and tumour necrosis factor in leukocyte recruitment to acute dermal inflammation

1992 ◽  
Vol 1 (5) ◽  
pp. 347-353 ◽  
Author(s):  
Andrew C. Issekutz ◽  
Nancy Lopes ◽  
Thomas B. Issekutz
Keyword(s):  
Monoclonal Antibody ◽  
Umbilical Vein ◽  
Interleukin 1 ◽  
E Coli ◽  
Tnf Α ◽  
Lps Activation ◽  
Necrosis Factor

The cytokines IL-1 and TNF-α are involved in inflammation and their production is stimulated by various agents, especially endotoxin (LPS). Here, using the human IL-1 receptor antagonist (IL-1RA) and a new monoclonal antibody (mAb 7F11) to rabbit TNF, the role of endogenous IL-l and TNF production in acute (3h) leukocyte (PMNL) recruitment to dermal inflammation in rabbits has been studied. IL-1RA inhibited by 27% the PMNL accumulation in reactions induced by killed Escherichia coli (p < 0.05) but not by LPS. The monoclonal antibody to TNF inhibited by 27% and 38% (p < 0.002) the PMNL accumulation in LPS and E. coli reactions respectively, but a combination of the mAb with IL-1RA was not more effective. Treatment of human umbilical vein endothelium with LPS for 3 h activated endothelium to induce PMNL transendothelial migration in vitro, which was not inhibited by IL-1RA, antibody to TNF-α, IL-1 or to IL-8. In conclusion, TNF and IL-1 may partially mediate acute PMNL infiltration in vivo to LPS and Gram negative bacteria, but there is a major IL-1/TNF independent mechanism, at least in dermal inflammation, which may be due to direct LPS activation of the microvasculature or perhaps the generation of cytokines other than IL-1 and TNF.

Bacterial lipopolysaccharide directly induces angiogenesis through TRAF6-mediated activation of NF-κB and c-Jun N-terminal kinase

Blood ◽  
2003 ◽  
Vol 102 (5) ◽  
pp. 1740-1742 ◽  
Author(s):  
Ingrid Pollet ◽  
Christy J. Opina ◽  
Carla Zimmerman ◽  
Kevin G. Leong ◽  
Fred Wong ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Tumor Necrosis Factor Receptor ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Bacterial Lipopolysaccharide ◽  
Intracellular Signaling Pathway ◽  
Necrosis Factor

AbstractThe intracellular pathways by which inflammatory mediators transmit their angiogenic signals is not well studied. The effects of a potent inflammatory mediator, bacterial lipopolysaccharide (LPS), are transmitted through Toll-like receptors (TLRs). A major, although not exclusive, LPS/TLR intracellular signaling pathway is routed through TNF (tumor necrosis factor) receptor associated factor 6 (TRAF6). In this report we demonstrate that LPS directly stimulates endothelial sprouting in vitro. By blocking TRAF6 activity using retroviral expression of a dominant-negative TRAF6 in endothelial cells, we show that TRAF6 is absolutely required for the LPS-initiated angiogenic response in vitro and in vivo. Inhibition of either c-Jun N-terminal kinase (JNK) activity or nuclear factor κB (NF-κB) activity, downstream of TRAF6, is sufficient to inhibit LPS-induced endothelial sprouting. In contrast, only inhibition of NF-κB, but not JNK, activity blocks basic fibroblast growth factor (bFGF)–induced angiogenesis. Our findings thus demonstrate a direct endothelial-stimulatory role of LPS in initiating angiogenesis through activation of TRAF6-dependent signaling pathways.

scholarly journals Construction of a ribozyme directed against human interleukin-6 mRNA: evaluation of its catalytic activity in vitro and in vivo

Blood ◽  
1994 ◽  
Vol 84 (11) ◽  
pp. 3758-3765 ◽  
Author(s):  
M Mahieu ◽  
R Deschuyteneer ◽  
D Forget ◽  
P Vandenbussche ◽  
J Content
Keyword(s):  
Interleukin 6 ◽  
Ribonuclease Protection Assay ◽  
Mammalian Expression ◽  
Cell Clones ◽  
Ribonuclease Protection ◽  
Amniotic Cells ◽  
Necrosis Factor

We have designed a ribozyme (Rz) that cleaves human interleukin-6 (IL- 6) mRNA in vivo. This Rz was tested in vitro, and was found to give expected size fragments. It was then incorporated into a mammalian expression vector containing the constitutive cytomegalovirus (CMV) immediate early promoter and transfected into human U amniotic cells (UAC). Cell clones that stably express this catalytic RNA have been obtained. Some of them displayed a marked reduction of tumor necrosis factor (TNF)-induced IL-6 production. Their reduced ability to express IL-6 was related to the amount of Rz they produced and to the extent of IL-6 mRNA cleavage as observed by a ribonuclease protection assay. These data provide a method to study further the role of IL-6 production in various biologic situations, and suggest the feasibility of developing Rzs directed against various cytokines to study their biologic role and mechanism of action.

Angiotensin II binding sites in aortic endothelium of domestic fowl

1990 ◽  
Vol 258 (3) ◽  
pp. R777-R782 ◽  
Author(s):  
J. N. Stallone ◽  
H. Nishimura ◽  
A. Nasjletti
Keyword(s):  
Angiotensin Ii ◽  
Domestic Fowl ◽  
Angiotensin Receptors ◽  
Ang Ii ◽  
Aortic Endothelium ◽  
Specific Receptors ◽  
Layer Chromatography

In domestic fowl, angiotensin II (ANG II) produces a unique vasodepressor response in vivo and endothelium-dependent relaxation of aortic rings in vitro that appear to be a direct effect on vascular smooth muscle mediated through vascular angiotensin receptors. To explore the possible role of the endothelium in ANG II-induced vasodilation, ANG II binding to aortic membrane fractions and intact endothelium and prostaglandin (PG) production were examined in fowl aortas. 125I-[Ile5]ANG II binding by endothelium-intact aortic membrane fractions was consistently higher than binding by identically prepared endothelium-deleted membrane fractions at virtually all concentrations of ligand (10 pM-0.20 microM). Incubation of intact aortic rings with 125I-[Ile5]ANG II (0.50 nM) resulted in specific endothelial binding that increased linearly with time from 5.5 +/- 1.7 (SE) fmol/mg protein at 5 min to 13.7 +/- 1.8 at 30 min. Endothelial ANG II binding increased linearly with the dose of ligand, from 2.7 +/- 0.3 fmol/mg protein at 0.1 nM to 21.0 +/- 2.2 at 1.0 nM. Specific ANG II binding to aortic endothelium was competitively displaced 73 +/- 11% by unlabeled ANG II (0.1 microM) but not by bradykinin (0.1 microM). Incubation of intact aortic rings with [14C]arachidonic acid resulted in the formation of radioactive metabolites that comigrated in thin-layer chromatography with authentic PGE2 but not with 6-keto-PGF1 alpha. PGE2 production by aortic rings (44.4 +/- 4.5 ng.mg dry tissue-1.h-1) was not stimulated by addition of ANG II. These results suggest that specific receptors for ANG II exist in fowl aortic endothelium and that PGs are not involved in ANG II-induced vasodilation of the fowl aorta.

scholarly journals Role of Vitamin E and the Orexin System in Neuroprotection

2021 ◽  
Vol 11 (8) ◽  
pp. 1098
Author(s):  
Maria Ester La Torre ◽  
Ines Villano ◽  
Marcellino Monda ◽  
Antonietta Messina ◽  
Giuseppe Cibelli ◽  
...  
Keyword(s):  
Vitamin E ◽  
Neurodegenerative Diseases ◽  
Antioxidant Properties ◽  
Phenotypic Change ◽  
The Central Nervous System ◽  
Specific Receptors

Microglia are the first line of defense at the level of the central nervous system (CNS). Phenotypic change in microglia can be regulated by various factors, including the orexin system. Neuroinflammation is an inflammatory process mediated by cytokines, by the lack of interaction of specific receptors such as the OX2-OX2R complex, caused by systemic tissue damage or, more often, associated with direct damage to the CNS. Chronic activation of microglia could lead to long-term neurodegenerative diseases. This review aims to explore how tocopherol (vitamin E) and the orexin system may play a role in the prevention and treatment of microglia inflammation and, consequently, in neurodegenerative diseases thanks to its antioxidant properties. The results of animal and in vitro studies provide evidence to support the use of tocopherol for a reduction in microglia inflammation as well as a greater activation of the orexinergic system. Although there is much in vivo and in vitro evidence of vitamin E antioxidant and protective abilities, there are still conflicting results for its use as a treatment for neurodegenerative diseases that speculate that vitamin E, under certain conditions or genetic predispositions, can be pro-oxidant and harmful.

scholarly journals Expression of lymphotoxin-αβ on antigen-specific T cells is required for DC function

2007 ◽  
Vol 204 (5) ◽  
pp. 1071-1081 ◽  
Author(s):  
Leslie E. Summers-deLuca ◽  
Douglas D. McCarthy ◽  
Bojana Cosovic ◽  
Lesley A. Ward ◽  
Calvin C. Lo ◽  
...  
Keyword(s):  
T Cells ◽  
Lymphoid Tissue ◽  
Tumor Necrosis ◽  
Dc Function ◽  
Tissue Organization ◽  
Tnf Superfamily ◽  
Draining Lymph Node ◽  
Necrosis Factor

During an immune response, activated antigen (Ag)-specific T cells condition dendritic cells (DCs) to enhance DC function and survival within the inflamed draining lymph node (LN). It has been difficult to ascertain the role of the tumor necrosis factor (TNF) superfamily member lymphotoxin-αβ (LTαβ) in this process because signaling through the LTβ-receptor (LTβR) controls multiple aspects of lymphoid tissue organization. To resolve this, we have used an in vivo system where the expression of TNF family ligands is manipulated only on the Ag-specific T cells that interact with and condition Ag-bearing DCs. We report that LTαβ is a critical participant required for optimal DC function, independent of its described role in maintaining lymphoid tissue organization. In the absence of LTαβ or CD40L on Ag-specific T cells, DC dysfunction could be rescued in vivo via CD40 or LTβR stimulation, respectively, suggesting that these two pathways cooperate for optimal DC conditioning.

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