Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Repetitive administration of low doses of tumor necrosis factor (TNF) induces a selective tolerance to some, but not all, of its effects. The aim of the present study was to define the pathways involved in tolerance. We observed that the induction of tolerance is mediated by TNF-R55 triggering. TNF-R75 triggering or the addition of sensitizers can interfere with this induction but does not break an acquired tolerance, inasmuch as tolerant animals were also tolerant to otherwise lethal challenges with the combination of human TNF and the sensitizers interleukin-1 and RU-38486. We further defined the selectivity of the tolerance by examining changes in quantitative parameters such as interleukin-6 induction, hypothermia, and hemoconcentration. The differences between tolerant and nontolerant animals mimicked those observed after administration of human TNF vs. murine TNF and were to be found in the duration rather than in the amplitude of the induced changes. We conclude that tolerance selectively blocks the TNF-R75-mediated pathway, especially the part mimicked by interleukin-1 and RU-38486; this pathway normally leads to a state of unresponsiveness to glucocorticoids.
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PMID:Mechanism of tolerance to tumor necrosis factor: receptor-specific pathway and selectivity. 765 62

Infection of susceptible mice with Plasmodium berghei Anka leads to a syndrome of severe or cerebral malaria. Tumor necrosis factor (TNF) contributes to this syndrome, apparently by acting on its receptor 2 (TNFR2) because TNFR1-/- are susceptible, whereas TNFR2-/- mice are resistant. In this work, we confirmed the essential role of the TNFR2 in cerebral malaria because 6 to 8 days after Plasmodium berghei Anka infection, hypothermia, coma, and death were observed in +/+ or TNFR1-/-, but never in TNFR2-/-, mice. TNF production, evaluated by the serum levels or the mRNA levels in the brain, spleen or lung, was similar in +/+, TNFR1-/-, or TNFR2-/- mice. Macrophage or parasitized red blood cell sequestration in brain or lung was similar in TNFR1-/- and TNFR2-/- mice. Accordingly, up-regulation of CD54 or CD40 in brain or lung was also similar in TNFR1-/- or TNFR2-/- mice. Platelet loss, manifested by thrombocytopenia and the presence of microparticles in plasma, was similar in TNFR1-/- or TNFR2-/- mice. Breakdown of the blood-brain barrier, detected by the diffusion of tracers, was attenuated in both TNFR1-/- and TNFR2-/-, compared with +/+, mice. Endothelial cells from brain capillaries, examined by transmission electron microscopy, were similar in infected TNFR1-/- or TNFR2-/- mice, whereas the basement membrane was enlarged in TNFR1-/- mice. Hypothermic mice were also hyperglycemic, and this was evident in +/+ and TNFR1-/-, but not in TNFR2-/-, mice. In addition, infected +/+ and TNFR1-/- mice became insulin resistant, while in contrast TNFR2-/- became extremely insulin sensitive. This study supports the possibility that coma and death are mediated not by cell sequestration or breakdown of vascular permeability, similar in TNFR1-/- or TNFR2-/- mice, but by metabolic disturbances selectively mediated by the TNFR2.
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PMID:Role of the tumor necrosis factor receptor 2 (TNFR2) in cerebral malaria in mice. 1221 76

Tumor necrosis factor (TNF)-alpha, a cardinal molecule in the cascade of sepsis-induced host injury, binds to two distinct receptors: tumor necrosis factor receptor (TNFR) 1 and TNFR2. We used the cecal ligation and puncture model of polymicrobial sepsis to elucidate the role of these receptors in sepsis pathogenesis. Mice lacking TNFR1 had prolonged survival with less hypothermia, whereas mice lacking TNFR2-/- had shortened survival and more profound hypothermia than wild-type mice. TNFR1-/- and TNFR2-/- mice had increased serum concentrations of interleukin (IL) 1beta and total TNF-alpha (free plus receptor bound) compared with wild-type mice, but there were no differences in IL6 or IL10 concentrations. Furthermore, free TNF-alpha was markedly elevated in the serum and peritoneal fluid of mice lacking TNFR2, supporting a role for this receptor in regulating the concentration of TNF-alpha. Lastly, apoptosis of ileal crypt epithelial cells was increased in mice lacking TNFR1, but there were no differences in lymphocyte apoptosis. These data suggest that in sepsis, TNFR1 mediates much of the TNF-alpha-induced pathology, whereas TNFR2 mediates protective effects.
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PMID:Opposing effects of tumor necrosis factor receptor 1 and 2 in sepsis due to cecal ligation and puncture. 1580 53