Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific.

Lewis, Martyn; Tartaglia, Louis A.; Lee, Angela; Bennett, Gregory L.; Rice, Glenn C.; Wong, Grace; Chen, Ellson Y.; Goeddel, David V.

doi:10.1073/pnas.88.7.2830

Cited by 500 publications

(281 citation statements)

References 43 publications

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“…These results were confirmed by qPCR, which showed that livers of Tnfr sf1a +/-mice had about half of the p55TNFR mRNA of Tnfrsf1a +/+ mice (Supplemental Figure 1G). Binding studies using I 125 -labeled human TNF ( 125 I-hTNF), which binds mouse p55TNFR (mp55-TNFR) but not mouse p75TNFR (33), showed that binding is reduced by about half in Tnfrsf1a +/-bone marrow-derived macrophages (BMDMs) compared with Tnfrsf1a +/+ BMDMs ( Figure 1G). Finally, p55TNFR expression was measured on Tnfrsf1a +/-cells by FACS and was intermediate between Tnfrsf1a +/+ and Tnfrsf1a -/-BMDMs (Supplemental Figure 1H).…”

Section: A 50% Reduction Of P55tnfr Completely Protects Mice Against mentioning

confidence: 99%

Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium

Hauwermeiren¹,

Armaka²,

Karagianni³

et al. 2013

J. Clin. Invest.

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TNF has remarkable antitumor activities; however, therapeutic applications have not been possible because of the systemic and lethal proinflammatory effects induced by TNF. Both the antitumor and inflammatory effects of TNF are mediated by the TNF receptor p55 (p55TNFR) (encoded by the Tnfrsf1a gene). The antitumor effect stems from an induction of cell death in tumor endothelium, but the cell type that initiates the lethal inflammatory cascade has been unclear. Using conditional Tnfrsf1a knockout or reactivation mice, we found that the expression level of p55TNFR in intestinal epithelial cells (IECs) is a crucial determinant in TNFinduced lethal inflammation. Remarkably, tumor endothelium and IECs exhibited differential sensitivities to TNF when p55TNFR levels were reduced. Tumor-bearing Tnfrsf1a +/-or IEC-specific p55TNFR-deficient mice showed resistance to TNF-induced lethality, while the tumor endothelium remained fully responsive to TNF-induced apoptosis and tumors regressed. We demonstrate proof of principle for clinical application of this approach using neutralizing anti-human p55TNFR antibodies in human TNFRSF1A knockin mice. Our results uncover an important cellular basis of TNF toxicity and reveal that IEC-specific or systemic reduction of p55TNFR mitigates TNF toxicity without loss of antitumor efficacy.

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Section: A 50% Reduction Of P55tnfr Completely Protects Mice Against mentioning

confidence: 99%

Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium

Hauwermeiren¹,

Armaka²,

Karagianni³

et al. 2013

J. Clin. Invest.

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“…Although, the amino acid sequence homology between mouse and human TNFαισ 79% [81], mouse TNFα (mTNFα) is a glycosylated dimer whereas human TNFα (hTNFα) is not glycosylated [82]. hTNFα does not bind to mouse type 2 TNF receptors (mTNF-R2), whereas mTNFα binds to both mTNF-R1 and mTNF-R2 [83]. Therefore, hTNFα lacks some of the actions of mTNFα in mice [84], so that physiologically relevant effects can only be studied using the homologous cytokines.…”

Section: Tumor Necrosis Factor-αmentioning

confidence: 99%

Effects of cytokines and infections on brain neurochemistry

Dunn

2006

Clinical Neuroscience Research

273

168

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Administration of cytokines to animals can elicit many effects on the brain, particularly neuroendocrine and behavioral effects. Cytokine administration also alters neurotransmission, which may underlie these effects. The most well studied effect is the activation of the hypothalamopituitary-adrenocortical (HPA) axis, especially that by interleukin-1 (IL-1). Peripheral and central administration of IL-1 also induces norepinephrine (NE) release in the brain, most markedly in the hypothalamus. Small changes in brain dopamine (DA) are occasionally observed, but these effects are not regionally selective. IL-1 also increases brain concentrations of tryptophan, and the metabolism of serotonin (5-HT) throughout the brain in a regionally nonselective manner. Increases of tryptophan and 5-HT, but not NE, are also elicited by IL-6, which also activates the HPA axis, although it is much less potent in these respects than IL-1. IL-2 has modest effects on DA, NE and 5-HT. Like IL-6, tumor necrosis factor-α (TNFα) activates the HPA axis, but affects NE and tryptophan only at high doses. The interferons (IFN's) induce fever and HPA axis activation in man, but such effects are weak or absent in rodents. The reported effects of IFN's on brain catecholamines and serotonin have been very varied. However, interferon-γ, and to a lesser extent, interferon-α, have profound effects on the catabolism of tryptophan, effectively reducing its concentration in plasma, and may thus limit brain 5-HT synthesis.Administration of endotoxin (LPS) elicits responses similar to those of IL-1. Bacterial and viral infections induce HPA activation, and also increase brain NE and 5-HT metabolism and brain tryptophan. Typically, there is also behavioral depression. These effects are strikingly similar to those of IL-1, suggesting that IL-1 secretion, which accompanies many infections, may mediate these responses. Studies with IL-1 antagonists, support this possibility, although in most cases the antagonism is incomplete, suggesting the existence of multiple mechanisms. Because LPS is known to stimulate the secretion of IL-1, IL-6 and TNFα, it seems likely that these cytokines mediate at least some of the responses, but studies with antagonists indicate that there are multiple mechanisms. The neurochemical responses to cytokines are likely to underlie the endocrine and behavioral responses. The NE response to IL-1 appears to be instrumental in the HPA activation, but other mechanisms exist. Neither the noradrenergic nor the serotonergic systems appear to be involved in the major behavioral responses. The significance of the serotonin response is unknown.

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“…TNFα exerts its effect via two receptors, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2) (Lewis et al 1991;Tartaglia et al 1993;Tartaglia et al 1991). These receptors are localized on neurons, including the nigral neurons, as well as on glial cells (Boka et al 1994;Dziewulska and Mossakowski 2003;McGuire et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Dual effects of TNFα on nerve fiber formation from ventral mesencephalic organotypic tissue cultures

Marschinke

Strömberg

2008

Brain Research

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Tumor necrosis factor alpha (TNFα) is toxic to dopamine neurons and increased levels of TNFα are observed in Parkinson's disease. Dopamine nerve fiber outgrowth in organotypic cultures of fetal ventral mesencephalon occurs in two waves. The early appearing nerve fibers are formed in the absence of astroglia, while migrating astrocytes guide the late appearing dopamine nerve fibers. TNFα (40 ng/ml) was added to the medium of organotypic ventral mesencephalic tissue cultures between days 4-7 or 11-14. The cultures were evaluated at days 7 or 19 to study effects of TNFα on both types of nerve fiber formation. Tyrosine hydroxylase (TH) -immunohistochemistry demonstrated that the number of cultures showing non-glial-guided TH-positive outgrowth was reduced compared to controls, when TNFα was added at day 4. By contrast, the glial-guided THpositive nerve fiber outgrowth and the astrocytic migration reached significantly longer distances by early TNFα treatment. Ki67-immunohistochemistry revealed that TNFα did not affect proliferation of astrocytes. Treatment with TNFα and antibodies against TNFα receptor 1 between days 4-7 revealed that the non-glial-guided TH-positive outgrowth reappeared. TNFα treatment between days 11-14 triggered neither the TH-positive glial-guided outgrowth, nor promoted the astrocytic migration to reach longer distances. The number of microglia was significantly increased after the late but not early TNFα treatment. In conclusion, TNFα is toxic for the non-glial dopaminergic nerve fiber outgrowth but stimulates the glial-guided outgrowth and the migration of astrocytes at an early time point. TNFα increased the number of microglia in VM tissue cultures after late but not after early treatment.

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Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific.

Cited by 500 publications

References 43 publications

Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium

Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium

Effects of cytokines and infections on brain neurochemistry

Dual effects of TNFα on nerve fiber formation from ventral mesencephalic organotypic tissue cultures

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