A wake-like state in vitro induced by transmembrane TNF/soluble TNF receptor reverse signaling

2021 ◽  
Vol 94 ◽  
pp. 245-258
Author(s):  
Cheryl Dykstra-Aiello ◽  
Khia Min Sabrina Koh ◽  
Joseph Nguyen ◽  
Mengran Xue ◽  
Sandip Roy ◽  
...  
Keyword(s):  
Tnf Receptor ◽  
Reverse Signaling ◽  
Soluble Tnf Receptor

scholarly journals 0017 Transmembrane TNF- Soluble TNF Receptor Reverse Signal to Induce a Wake-Like State in Vitro

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A7-A7
Author(s):  
C J Dykstra-Aiello ◽  
K Koh ◽  
J Nguyen ◽  
J M Krueger
Keyword(s):  
Cortical Neurons ◽  
Action Potentials ◽  
State Regulation ◽  
Electrode Arrays ◽  
Electrophysiological Properties ◽  
Reverse Signaling ◽  
Soluble Tnf Receptor ◽  
Induced Changes

Abstract Introduction Tumor necrosis factor (TNF) has sleep regulatory roles. Neuronal action potentials enhance TNF expression. Neuron/glia co-cultures exhibit more intense local sleep-like states after TNF administration in vitro. Both TNF and TNF receptors (Rs) are produced as transmembrane (tm) proteins that can subsequently be cleaved to produce soluble (s) forms. With immunocytes, sTNFR can bind tmTNF and induce reverse signaling within the cell expressing the tmTNF. This is opposite of conventional signaling induced by soluble ligands (e.g. sTNF) binding to transmembrane receptors. Having previously shown sleep inhibition after sTNFR administration in vivo, we hypothesized that tmTNF-sTNFR binding would induce wake-like states in vitro through reverse signaling. Methods Somatosensory cortical neurons/glia, from wildtype (WT) mice and mice lacking either TNF (TNF-KO) or both TNFRs (TNFR-KO), were co-cultured on multi-electrode arrays. Daily one-hour recordings were taken consecutively on incubation days 4 - 13 for development analyses. On day 14, a one-hour baseline was recorded prior to treatment with sTNFR (0.0 ng/μL-120 ng/μL). Immediately after treatment, recordings resumed for one hour. Synchronization of electrical activity (SYN), action potentials, slow wave power (SWP; 0.25–3.75 Hz), and burstiness index (measures used to define sleep in vivo) were used to characterize the ontological emergence of these electrophysiological properties and sTNFR-induced changes in vitro. Results Development rates were reduced in TNF-KO cells and increased in TNFR-KO cells relative to each other and to WT mice. Additionally, after sTNFR treatments, cells from TNFR-KO mice, which still express TNF, exhibited dose-dependent decreased SYN and SWP, indicative of a wake-like state. In contrast, cells from TNF-KO mice lacked a response to sTNFR treatment. Conclusion To our knowledge, this is the first demonstration of reverse TNF signaling with respect to sleep/wake states. As such, it provides a new way of viewing state regulation and associated potential clinical applications. Support This work was supported by grant NS096250 awarded to JK by NIH/NINDS.

Does pravastatin affect circulating levels of soluble TNF receptor 2 in hypercholesterolemic patients?

2003 ◽  
Vol 166 (2) ◽  
pp. 413-414 ◽  
Author(s):  
Hitoshi Ando ◽  
Toshinari Takamura ◽  
Ken-ichi Kobayashi ◽  
Hirofumi Misu ◽  
Kenso Osawa
Keyword(s):  
Tnf Receptor ◽  
Soluble Tnf Receptor ◽  
Circulating Levels

scholarly journals CD28-independent, TRAF2-dependent Costimulation of Resting T Cells by 4-1BB Ligand

1998 ◽  
Vol 187 (11) ◽  
pp. 1849-1862 ◽  
Author(s):  
Katina Saoulli ◽  
Soo Young Lee ◽  
Jennifer L. Cannons ◽  
Wen Chen Yeh ◽  
Angela Santana ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Expression System ◽  
Baculovirus Expression System ◽  
Dominant Negative ◽  
Soluble Form ◽  
Tnf Receptor

4-1BB ligand (4-1BBL) is a member of the tumor necrosis factor (TNF) family expressed on activated antigen-presenting cells. Its receptor, 4-1BB, is a member of the TNF receptor family expressed on activated CD4 and CD8 T cells. We have produced a soluble form of 4-1BBL using the baculovirus expression system. When coimmobilized on plastic with anti-CD3, soluble 4-1BBL induces interleukin (IL)-2 production by resting CD28+ or CD28− T cells, indicating that 4-1BBL can function independently of other cell surface molecules, including CD28, in costimulation of resting T cell activation. At low concentrations of anti-CD3, 4-1BBL is inferior to anti-CD28 in T cell activation. However, when 4-1BB ligand is provided together with strong TCR signals, then 4-1BBL and anti-CD28 are equally potent in stimulation of IL-2 production by resting T cells. We find that TNF receptor–associated factor (TRAF)1 or TRAF2 associate with a glutathione S-transferase–4-1BB cytoplasmic domain fusion protein in vitro. In T cells, we find that association of TRAF1 and TRAF2 with 4-1BB requires 4-1BB cross-linking. In support of a functional role for TRAF2 in 4-1BB signaling, we find that resting T cells isolated from TRAF2-deficient mice or from mice expressing a dominant negative form of TRAF2 fail to augment IL-2 production in response to soluble 4-1BBL. Thus 4-1BB, via the TRAF2 molecule, can provide CD28-independent costimulatory signals to resting T cells.

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.

P826Peri-procedural treatment with high dose Rosuvastatin reduces soluble TNF receptor 1 in patients treated with primary percutaneous coronary intervention for ST elevation myocardial infarction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A I Larsen ◽  
N Butt ◽  
P Aukrust ◽  
P S Munk ◽  
J M Nilsen ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Percutaneous Coronary Intervention ◽  
Primary Percutaneous Coronary Intervention ◽  
Inflammatory Markers ◽  
Coronary Intervention ◽  
High Dose ◽  
Tnf Receptor ◽  
Percutaneous Coronary ◽  
St Elevation ◽  
Soluble Tnf Receptor

Abstract Background The extent of cardiac injury in ST elevation myocardial infarction (STEMI) depends on the level of inflammation and subsequent immune cell recruitment. An inflammatory phase that is disproportionately prolonged, of excessive magnitude, or insufficiently suppressed, can lead to sustained tissue damage and improper healing, promoting infarct expansion, adverse remodelling and chamber dilatation. Soluble TNF receptor 1 (sTNFR-1) is believed to mirror systemic pan-inflammatory status more closely than a single cytokine antigenic level. sTNFR-1 levels might give prognostic information, independent from and, at the same time, additive with some well-recognized outcome predictors such as left ventricular ejection fraction. Purpose We hypothesised that sTNFR-1 and other inflammatory markers could be modulated by statins. Methods Plasma levels of inflammatory markers were measured at baseline, 2 days, 7 days and 2 months in consecutive patients with first time STEMI with single vessel disease. Twenty-five patients (treatment group (TG)) were treated with 80 mg Rosuvastatin daily with first dose before primary percutaneous coronary intervention (PCI) whereas the control group (CG) consisted of 34 patients in whom treatment with 20 mg simvastatin daily were initiated the day after PPCI. Results sTNFR1 increased during the first 48 hours following PCI and this increase was larger in the CG compared with the TG (0.22±0.30 ng/mL vs 0.08±0.19 ng/nmL, p=0.025). The difference in increase during one week was only borderline statistically significant (0.21±0.30 ng/mL vs 0.08±0.26 ng/mL, p=0.081). These differences in the kinetics of sTNRF-1 were mirrored by changes in Pentraxin 3 (PTX3) between groups from baseline to 1 week, CG vs TG. (0.28±0.70 μmol/l vs 0.10±0.05 ng/mL, p=0.014) and at 2 months (−0.42±0.56 ng/mL vs 0.08±0.60 μmol/l, p=0.032) Conclusion High dose Rosuvastatin therapy initiated peri-procedural during PPCI for STEMI reduces pan inflammation as reflected by sTNFR1 and is associated with a less abrupt fall in PTX3 at 1 week and 2 months supporting recent research suggesting that PTX3 plays a cardiovascular protective effect in cardiovascular disease and healing. Acknowledgement/Funding Western Norway Regional Health Authority

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