Tolerance to tumor necrosis factor in rats and the relationship to endotoxin tolerance and toxicity.

Fraker, Douglas L.; Stovroff, Mark C.; Merino, María J.; Norton, Jeffrey A.

doi:10.1084/jem.168.1.95

Cited by 178 publications

(85 citation statements)

References 19 publications

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“…In contrast to our results, Norton et al [27] demonstrated that TNF-a was capable of inducing tolerance to LPS. This discrepancy could be the result of a different animal model (rat), and/ or the fact that their experiments were carried out using an extremely high, and not physiological, dose of TNF-a (200 mg/kg/day for 5 consecutive days).…”

Section: Discussioncontrasting

confidence: 99%

Interleukin-1β inducesin vivotolerance to lipopolysaccharide in mice

Alves-Rosa

Vulcano

Beigier-Bompadre

et al. 2002

Clinical and Experimental Immunology

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SUMMARYEndotoxin or lipopolysaccharide (LPS) tolerance may be partially due to the secretion of potent antiinflammatory cytokines following severe Gram-negative infections, or by low doses of LPS. In this work, we describe the effects of interleukin-1b (IL-1b) and tumour necrosis factor alpha (TNF-a), two early cytokines secreted after LPS exposure, in the induction of LPS tolerance. Our results demonstrate that mice treated with three daily doses of 100 ng of IL-1b were tolerant to LPS-induced shock. However, TNF-a was unable to induce an LPS refractory state. Given the fact that 100 ng of IL-1b increase the plasma levels of glucocorticoids, we evaluated whether a daily injection of dexamethasone (DEX) alone was able to reproduce the LPS-like tolerant state. However, no signs of LPS refractoriness were detected, except when DEX was administered concomitantly with a dose of IL-1b that does not induce corticosterone secretion (12 ng/mouse). This dose was found to induce in vitro up-regulation of the glucocorticoid receptors (GcR) of peritoneal macrophages following 24 h of treatment. In addition, we demonstrate that IL-1b is capable of inducing the down-regulation of Toll-like receptor 4 (TLR4), a crucial molecule in the signal transduction of LPS. Taken together, our results indicate that IL-1b can generate tolerance to LPS in vivo, and suggest that the regulation of mechanisms of the downregulation of TLR4, as well as those involved in the expression of GcR and/or in the secretion of glucocorticoids, would be crucial for these effects.

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Section: Discussioncontrasting

confidence: 99%

Interleukin-1β inducesin vivotolerance to lipopolysaccharide in mice

Alves-Rosa

Vulcano

Beigier-Bompadre

et al. 2002

Clinical and Experimental Immunology

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“…Tolerance to TNF has been demonstrated in animals, 12 and has been suggested to occur in humans 13 based on the evidence that when tumor patients were treated with TNF-␣, they became refractory to its side effects after repeated exposure. 14 Therefore, the evidence presented in this study, may be the first to support the existence of tolerance to autologous TNF-␣ in humans.…”

Section: Resultsmentioning

confidence: 99%

Demonstration of anti-disease immunity to Plasmodium vivax malaria in Sri Lanka using a quantitative method to assess clinical disease.

Karunaweera¹,

Carter²,

Grau³

et al. 1998

The American Journal of Tropical Medicine and Hygiene

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Abstract. Clinical immunity to malaria was studied by quantifying the intensity of symptoms as well as by measurement of several hematologic indicators of pathology (the erythrocyte sedimentation rate [ESR], serum bilirubin, reticulocyte count, plasma tumor necrosis factor-␣ [TNF-␣], and blood glucose levels) in 39 Plasmodium vivax malaria patients exposed to endemic malaria in southern Sri Lanka, and for comparison in 43 nonimmune patients who were residents of nonmalarious regions of the country. The intensity of 11 symptoms was scored numerically in all patients using a questionnaire. This clinical score was validated by introducing internal controls to the questionnaire, and by correlating it with the underlying pathology. Both the intensity of clinical disease as well as the degree of underlying pathology were found to be significantly lower in endemic area patients (mean clinical score ϭ 8.8, median ESR ϭ 8 mm) compared with the nonendemic area patients (mean clinical score ϭ 19.0, median ESR 31.5 mm). Endemic area patients also had lower parasite densities (mean ϭ 0.06%) than those from the nonendemic area (0.12%) (P Ͻ 0.05). However, at any parasite density, both clinical disease and pathology were significantly less in the endemic area patients (P Ͻ 0.001, for both clinical score and ESR), indicating that the clinical immunity seen in the endemic area patients was a true tolerance of parasites. Although plasma TNF-␣ levels were elevated in both groups of patients, they were significantly higher in the nonendemic area patients than in patients from the endemic area (P Ͻ 0.01). Furthermore, at comparable levels of plasma TNF-␣, nonendemic area patients had both a higher intensity of clinical disease and an underlying pathology than those from the endemic area, suggesting that if TNF-

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“…Up-regulation of other putative protective cytokines in untreated transgenic animals or after administration of Con A could also play a role in hepatic protection and remains to be elucidated. Such a cytokine stimulatory network has been reported for the induction of desensitization after repeated administration of endotoxin or TNF to rodents (53)(54)(55)(56). The exact mechanism of cytokine tolerance is not fully understood, but it has been proposed that in desensitized cells alteration of the signaling cascades, rather than down-regulation of the corresponding receptors, plays a role (57,58).…”

Section: Discussionmentioning

confidence: 99%

Chronic Inflammation and Protection from Acute Hepatitis in Transgenic Mice Expressing TNF in Endothelial Cells

Willuweit

Sass

Schöneberg

et al. 2001

The Journal of Immunology

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Endothelial activation is an important feature of many inflammatory diseases and has been implicated as the cause of vascular complications in disorders such as diabetes, atherosclerosis, and transplant rejection. One of the most potent activators of the endothelium is TNF, which can also be expressed by endothelial cells, causing a permanent, autocrine stimulatory signal. To establish a model of continuous endothelial activation and to elucidate the role of endothelial derived TNF in vivo, we generated transgenic mice expressing a noncleavable transmembrane form of TNF under the control of the endothelial-specific tie2 promoter. Adult tie2-transmembrane TNF-transgenic mice developed chronic inflammatory pathology in kidney and liver, characterized by perivascular infiltration of mononuclear cells into these organs. Along with the infiltrate, an up-regulation of the adhesion molecules ICAM-1 and VCAM-1, but not E-selectin, in the endothelium was observed. Despite predisposition to chronic inflammation these mice were protected from immune-mediated liver injury in a model of Con A-induced acute hepatitis. Although the blood levels of soluble TNF and IFN-γ were increased in transgenic animals after challenge with Con A, no damage of hepatocytes could be detected, as assessed by the lack of increase in plasma transaminase activities and the absence of TUNEL staining in the liver. We conclude that expression of transmembrane TNF in the endothelium causes continuous endothelial activation, leading to both proinflammatory and protective events.

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Tolerance to tumor necrosis factor in rats and the relationship to endotoxin tolerance and toxicity.

Cited by 178 publications

References 19 publications

Interleukin-1β inducesin vivotolerance to lipopolysaccharide in mice

Interleukin-1β inducesin vivotolerance to lipopolysaccharide in mice

Demonstration of anti-disease immunity to Plasmodium vivax malaria in Sri Lanka using a quantitative method to assess clinical disease.

Chronic Inflammation and Protection from Acute Hepatitis in Transgenic Mice Expressing TNF in Endothelial Cells

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