A leukotriene-dependent spleen-liver axis drives TNF production in systemic inflammation

2021 ◽  
Vol 14 (679) ◽  
pp. eabb0969
Author(s):  
Monique T. Fonseca ◽  
Eduardo H. Moretti ◽  
Lucas M. M. Marques ◽  
Bianca F. Machado ◽  
Camila F. Brito ◽  
...  
Keyword(s):  
Systemic Inflammation ◽  
Kupffer Cells ◽  
Proinflammatory Cytokine ◽  
Tumor Necrosis ◽  
Host Immunity ◽  
Splenic Macrophages ◽  
Cytokine Tumor Necrosis Factor ◽  
Necrosis Factor

Production of the proinflammatory cytokine tumor necrosis factor (TNF) must be precisely regulated for effective host immunity without the induction of collateral tissue damage. Here, we showed that TNF production was driven by a spleen-liver axis in a rat model of systemic inflammation induced by bacterial lipopolysaccharide (LPS). Analysis of cytokine expression and secretion in combination with splenectomy and hepatectomy revealed that the spleen generated not only TNF but also factors that enhanced TNF production by the liver, the latter of which accounted for nearly half of the TNF secreted into the circulation. Using mass spectrometry–based lipidomics, we identified leukotriene B4 (LTB4) as a candidate blood-borne messenger in this spleen-liver axis. LTB4 was essential for spleen-liver communication in vivo, as well as for humoral signaling between splenic macrophages and Kupffer cells in vitro. LPS stimulated the splenic macrophages to secrete LTB4, which primed Kupffer cells to secrete more TNF in response to LPS in a manner dependent on LTB4 receptors. These findings provide a framework to understand how systemic inflammation can be regulated at the level of interorgan communication.

scholarly journals Spontaneous production of tumor necrosis factor alpha by Kupffer cells of MRL/lpr mice.

1988 ◽  
Vol 168 (2) ◽  
pp. 789-794 ◽  
Author(s):  
D B Magilavy ◽  
J L Rothstein
Keyword(s):  
Kupffer Cells ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Short Term ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Necrosis Factor ◽  
Short Term Culture

We report that freshly isolated, unstimulated Kupffer cells (KC) from MRL/lpr female mice in short-term culture spontaneously produce high levels of TNF-alpha. TNF production was first detected in KC cultures at age 6 wk and increased with the age of the mice. Moreover, the levels of spontaneous TNF production by KC directly correlated with the age of the MRL/lpr mice. Although TNF production by KC could be induced with C. parvum in vivo or LPS in vitro in all nonautoimmune C3H/HeN, BALB/c, DBA/2, C57B16 mice, the only other strain in which spontaneous TNF production by KC was observed was MRL/++ mice greater than 10 mo old.

Oxyresveratrol dampens neuroimmune responses in vivo: a selective effect on TNF-α

2006 ◽  
Vol 291 (5) ◽  
pp. R1215-R1221 ◽  
Author(s):  
A. Mouihate ◽  
T. F. Horn ◽  
Q. J. Pittman
Keyword(s):  
Tumor Necrosis ◽  
Inflammatory Responses ◽  
Inhibitory Effect ◽  
Febrile Response ◽  
Pathological Conditions ◽  
Tnf Α ◽  
Cytokine Tumor Necrosis Factor ◽  
Necrosis Factor

Consumption of nutrients rich in hydroxystilbenes has been promoted because of their health benefits, including dampening of inflammatory responses. However, few studies have examined their effects in vivo. Here, we show that the hydroxystilbene oxyresveratrol (trans-2,3′,4,5′-tetrahydroxystilbene: o-RES) blocked hypothermia but caused no significant effect on the febrile response to the immune stimulus, bacterial LPS in rats. This was associated with a reduction in the LPS-induced plasma cytokine, tumor necrosis factor (TNF)-α, but not IL-6. Both IL-6-stimulated STAT-3 and LPS-induced cycoloxygenase-2 expression in the hypothalamus were not affected by o-RES. These data strongly suggest that the o-RES-induced dampening of neuroimmune responses is largely due to its inhibitory effect on TNF-α production. In contrast to in vitro experiments, o-RES has no direct effect on NF-κB signaling pathway in vivo. The specific inhibitory effect of o-RES on TNF-α opens new avenues for the clinical use of o-RES in pathological conditions where excessive production of TNF-α is deleterious.

Abstract 354: Lower Circulating Levels of Tumor Necrosis Factor Related Apoptosis-inducing Ligand (TRAIL) are Associated with Increased Sub-clinical Coronary Atherosclerosis among Smokers

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Aman Gupta ◽  
Divay Chandra ◽  
Yingze Zhang ◽  
Steven Reis ◽  
Frank Sciurba
Keyword(s):  
Tumor Necrosis Factor ◽  
Coronary Atherosclerosis ◽  
Tumor Necrosis ◽  
Smoking Status ◽  
Calcium Score ◽  
Meso Scale Discovery ◽  
The Mean ◽  
Necrosis Factor

Rationale: There is significant in vitro evidence demonstrating anti-atherogenic effect of circulating Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). Also, decreased circulating TRAIL levels have been reported in patients with acute myocardial infarction and in those undergoing coronary catheterization due to suspected coronary atherosclerosis. However, it remains unknown if TRAIL levels are associated with sub-clinical coronary atherosclerosis. Methods: The study included 460 current and former smokers enrolled in the Pittsburgh COPD SCCOR study. Serum TRAIL levels were measured by electrochemiluminescence immunoassay, according to the manufacture’s protocol (Meso Scale Discovery, Gaithersburg, Maryland). Coronary atherosclerosis was assessed by a validated visual coronary artery calcium scoring system using non-EKG gated chest CT scans (Weston score). Ordinal logistic regression models were used to identify significant associations between categories of CAC score (0, 1-3, 4-8, and 9-12) and TRAIL level, and to adjust for cardiovascular risk factors. Results: The mean age of the 460 participants was 65.7 ± 6.3 years, 52.2% were male, and the mean pack years of smoking was 55.0 ± 30.8 years. In univariate analyses, each standard deviation decrease in TRAIL levels was associated with 1.42-fold increase in the odds of having calcium scores in one higher category (p<0.001). This association persisted despite adjustment for age, gender, race, body mass index, hypertension, diabetes, hyperlipidemia, pack years of smoking, and current smoking status (adjusted OR for higher category of calcium score per SD decrease in TRAIL level 1.22, p=0.04). Conclusions: Our results expand on the in vitro and in vivo data linking decreased TRAIL levels with increased atherosclerosis by demonstrating a novel association between lower circulating TRAIL and increased subclinical coronary atherosclerosis.

Epinephrine inhibits endotoxin-induced IL-1β production: roles of tumor necrosis factor-α and IL-10

1997 ◽  
Vol 273 (6) ◽  
pp. R1885-R1890 ◽  
Author(s):  
Tom Van Der Poll ◽  
Stephen F. Lowry
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Ex Vivo ◽  
Systemic Infection ◽  
Tnf Α ◽  
Cytokine Tumor Necrosis Factor ◽  
Dose Dependent Decrease ◽  
Factor Α ◽  
Necrosis Factor

Epinephrine has been found to inhibit the production of the proinflammatory cytokine tumor necrosis factor (TNF)-α and to enhance the production of anti-inflammatory cytokine interleukin (IL)-10. To determine the effect of epinephrine on IL-1β production, the following experiments were performed: 1) blood obtained from subjects at 4–21 h after the start of a continuous infusion of epinephrine (30 ng ⋅ kg−1⋅ min−1) produced less IL-1β after ex vivo stimulation with lipopolysaccharide (LPS), compared with blood drawn from subjects infused with saline; 2) in whole blood in vitro, epinephrine caused a dose-dependent decrease in LPS-induced IL-1β production, which was likely mediated via adrenergic receptors; and 3) inhibition of TNF and enhancement of IL-10 both contributed to epinephrine-induced inhibition of IL-1β production. Epinephrine, either endogenously produced or administered as a component of sepsis treatment, may attenuate excessive activity of proinflammatory cytokines early in the course of systemic infection.

scholarly journals In Vivo and in Vitro Evidence for the Involvement of Tumor Necrosis Factor-α in the Induction of Leptin by Lipopolysaccharide*

Endocrinology ◽  
1998 ◽  
Vol 139 (5) ◽  
pp. 2278-2283 ◽  
Author(s):  
Brian N. Finck ◽  
Keith W. Kelley ◽  
Robert Dantzer ◽  
Rodney W. Johnson
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Factor Α ◽  
Necrosis Factor

Administration of tumor necrosis factor-alpha in vivo depresses endothelium-dependent relaxation

1994 ◽  
Vol 266 (6) ◽  
pp. H2535-H2541 ◽  
Author(s):  
P. Wang ◽  
Z. F. Ba ◽  
I. H. Chaudry
Keyword(s):  
Mean Arterial Pressure ◽  
Tumor Necrosis Factor ◽  
Arterial Pressure ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Vascular Relaxation ◽  
Endothelium Dependent Relaxation ◽  
Necrosis Factor

Although depressed endothelium-dependent relaxation occurs during early sepsis, the precise mechanism responsible for this remains unknown. Because the elevated levels of plasma tumor necrosis factor (TNF) play a major role in the pathophysiology of sepsis, we investigated whether TNF-alpha administration alters endothelium-dependent relaxation. To study this, recombinant TNF-alpha (1.2 x 10(7) U/mg) was infused intravenously (0.25 mg/kg body wt) for 0.5 h in normal rats, and mean arterial pressure was monitored. At 1 h after the completion of TNF-alpha or vehicle infusion, the aorta and a pulmonary artery were isolated, cut into 2.5-mm rings, and placed in organ chambers. Norepinephrine (2 x 10(-7) M) was applied to achieve near-maximal contraction, and dose responses for an endothelium-dependent vasodilator, acetylcholine, and an endothelium-independent vasodilator, nitroglycerine, were determined. In additional studies, aortic rings from normal animals were incubated with TNF-alpha for 2 h in vitro, and vascular reactivity was determined. The results indicate that TNF-alpha administration significantly reduced acetylcholine-induced vascular relaxation both in vivo and in vitro. Such a reduction was sustained at least 80 min after the completion of 2-h incubation with TNF-alpha. In contrast, TNF did not alter nitroglycerine-induced vascular relaxation. Thus TNF-alpha depresses endothelium-dependent relaxation in vitro as well as in vivo. Because TNF-alpha infusion increases plasma TNF levels without decreasing mean arterial pressure, the depressed endothelium-dependent relaxation observed during early sepsis may be due to the elevated circulating levels of TNF.

scholarly journals Gamma-interferon and tumor necrosis factor production after bone marrow transplantation is augmented by exposure to marrow fibroblasts infected with cytomegalovirus

Blood ◽  
1990 ◽  
Vol 76 (5) ◽  
pp. 1046-1053 ◽  
Author(s):  
AS Duncombe ◽  
A Meager ◽  
HG Prentice ◽  
JE Grundy ◽  
HE Heslop ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Tumor Necrosis Factor ◽  
Marrow Transplantation ◽  
Tumor Necrosis ◽  
Gamma Interferon ◽  
Cmv Infection ◽  
Necrosis Factor

Abstract After bone marrow transplantation (BMT), mortality from viral infections such as cytomegalovirus (CMV) remains high. Gamma-Interferon (gamma IFN) and tumor necrosis factor (TNF) are produced constitutively after BMT and have anti-viral properties. To study the effects of these cytokines on CMV interaction with host cells, we have used patient marrow fibroblasts since marrow stroma is a target for CMV infection correlating with myelosuppression in vivo. Both gamma IFN and TNF are constitutively produced by recipient CD3+ and CD16+ lymphocytes, but not by their marrow fibroblasts. Secretion by peripheral blood mononuclear cells is increased if they are cultured with host fibroblasts infected with CMV in vitro and the levels of gamma IFN and TNF produced are within the range that protects fresh fibroblasts from CMV infection. Constitutive secretion of cytokines by lymphocytes declines by 8 weeks after BMT, a time when the risk of CMV disease increases sharply. The in vitro phenomenon that we have described needs to be evaluated in correlative studies on individual BMT recipients to determine whether such a cytokine-mediated defense mechanism against CMV may operate in vivo.

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