Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have cloned the cDNAs of both human and mouse TNF and expressed them to high efficiency in Escherichia coli. Many transformed cell lines are sensitive to the cytotoxic action of TNF, especially in the presence of gamma-interferon, whereas normal cells either are unaffected or respond mitogenically. A number of human-mouse chimeric TNF genes have been constructed and expressed. All show biological activity but none of the chimeric proteins is neutralized by monoclonal antibodies to TNF. TNF has potent antitumour activity in nude mice carrying human xenografts or in mice bearing syngeneic tumours. In some systems direct effects can be demonstrated (in combination with species-specific gamma-interferon) but in others TNF acts indirectly. Combination of TNF with cytostatic drugs can also be effective in curing in vivo. The major limitation of the use of TNF is its toxicity. On many cell types TNF has an action similar to interleukin 1 (IL-1). At least some of the secondary, intracellular events may be identical for the two effectors. A possible mechanism of action of TNF is the release and metabolism of polyunsaturated fatty acids, which would explain the synthesis of prostaglandins and leukotrienes by many cell types after TNF treatment. The activation of the phospholipase can be blocked by corticoids. Some protease inhibitors protect cells from TNF-induced cytotoxicity but the target of these inhibitors has not been identified. Several genes are switched on by TNF (and by IL-1), including the gene for the 26 kDa protein recently identified as B cell stimulation factor 2. Events preceding death in rats include hypothermia, hypotension, acidosis and hypoglycaemia. All these effects can be largely eliminated by indomethacin pretreatment, with a resulting improvement in survival. As indomethacin does not inhibit the cytotoxic action of TNF on malignant cells it may form the basis for improved treatment protocols.
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PMID:Structure-function relationship of tumour necrosis factor and its mechanism of action. 313 Oct 72

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

The proinflammatory cytokines have been implicated in mediating myocardial dysfunction associated with myocardial infarction, severe congestive heart failure, and sepsis. We tested the hypothesis that cytokine levels are elevated after uncomplicated coronary artery bypass grafting and associated with episodes of postoperative myocardial ischemia and dysfunction. Coronary artery bypass grafting was performed under general anesthesia with moderate systemic hypothermia and cold-blood potassium cardioplegic solution. Tumor necrosis factor-alpha and interleukin-6 levels were determined by bioassays, and interleukin-8 levels were measured by a sandwich enzyme-linked immunosorbent assay. Myocardial function and ischemic episodes were assessed by intraoperative transesophageal echocardiography and perioperative 12-channel Holter monitoring. A total of 22 patients were studied, with no deaths or complications. Arterial tumor necrosis factor-alpha rose in a bimodal distribution, peaking at 2 and 18 to 24 hours after the operation (at 20.2 +/- 6.4 pg/ml, [mean +/- standard error of the mean]) and 5.8 +/- 1.6 pg/ml, respectively; before cardiopulmonary bypass: 0.90 +/- 0.20 pg/ml, p < 0.001 for both peaks) then progressively declined to levels before bypass. Arterial interleukin-6 was maximally elevated immediately on termination of cardiopulmonary bypass and peaked again 12 to 18 hours after cardiopulmonary bypass (at 7520 +/- 2439 pg/ml and 6216 +/- 1928 pg/ml, respectively; before bypass: 746 +/- 187 pg/ml, p < 0.0001 for both peaks). Arterial interleukin-8 levels were more variable but followed a similar pattern, peaking in the early period after cardiopulmonary bypass and again at 16 to 18 hours after the operation (at 4110 +/- 1403 pg/ml and 1760 +/- 1145 pg/ml, respectively; before bypass: 461 +/- 158, p < 0.05 for both peaks). By multivariate analysis, the aortic crossclamp time was independently predictive of postoperative cytokine levels. Left ventricular wall motion abnormalities were associated with both interleukin-6 and interleukin-8 levels, worsening scores being associated with increasing levels (for interleukin-6, p = 0.003; for interleukin-8, p = 0.05). Postoperative myocardial ischemic episodes were associated with interleukin-6 levels, six of seven (85%) patients with episodes of myocardial ischemia after a peak in interleukin-6 concentrations (p < 0.01). We conclude that proinflammatory cytokines are elevated after uncomplicated coronary revascularization and may contribute to postoperative myocardial ischemia and segmental wall motion abnormalities.
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PMID:Relationship of the proinflammatory cytokines to myocardial ischemia and dysfunction after uncomplicated coronary revascularization. 793 95

A 71-year-old woman remained under the rubble of her house for 4 hours after an accidental gas explosion. She suffered from a crush syndrome associating fractures, minor skin burns (< 10% body surface area), inhalation lung injury and moderate hypothermia (34 degrees C). In addition to local signs of compression of the lower limbs, the patient presented with hypovolemic shock and developed acute renal failure on day 3. We describe here the variations in hemodynamic and oxymetric parameters and cytokine response during the first post-injury week. A vasoplegic state resulting from low systemic vascular resistances with progressively increasing cardiac index, oxygen delivery and oxygen consumption closely followed the brief hypovolemic shock. Tumor necrosis factor-alpha remained below normal levels while interleukin-6 increased markedly with a major peak on day 2, in parallel with the drop in systemic vascular resistances. Interleukin-6 is a mediator of impairment in cell membrane function and a vasoconstriction inhibitor. Isolated increased interleukin-6 has been previously reported in severely burned patients suggesting a pathophysiological and hemodynamic similarity between crush syndrome and burn injury.
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PMID:[Hemodynamic profile and serum cytokines in crush syndrome. Analogy with severe burns]. 868 94

Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) have been implicated as key mediators in inflammation, morbidity, and mortality associated with sepsis. We examined the role of IL-6 and TNF-alpha signaling on hypothermia, fever, cachexia, anorexia, and survival during sepsis induced by cecal ligation and puncture (CLP) in male and female gene knockout mice. Male wild-type mice developed an initial hypothermia and subsequent fever during sepsis. Male IL-6 knockout mice did not develop fever; rather, they maintained a profound hypothermia during sepsis. Male TNF p55/p75 receptor (TNFR) knockout mice had attenuated hypothermia, but developed a virtually identical fever as wild-type mice. Cachexia did not differ between male wild-type and IL-6 or TNFR knockout mice, whereas anorexia was prolonged in IL-6 knockout mice. Due to the rapid lethality of sepsis in female mice, survival was the only variable we were able to statistically compare among female genotypes. Female wild-type mice had significantly decreased survival compared with male wild-type mice. Survival was significantly enhanced in male and female TNFR knockout mice compared with their wild-type controls. Lack of IL-6 did not affect male or female lethality. These data support the hypothesis that IL-6 is a key mediator of fever and food intake, whereas TNF is responsible for the initial hypothermia and lethality of sepsis in both sexes of mice. The enhanced lethality of CLP-treated female mice supports a role for sex steroids during sepsis.
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PMID:Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice. 968 88

Administration of recombinant murine tumor necrosis factor (TNF) to mice results in lethal shock, characterized by hypotension, hypothermia, and dramatic induction of cytokines released in the circulation, such as interleukin-6 (IL-6). The sensitivity of mice to the effects of murine TNF varies from strain to strain. DBA/2 mice were found to be considerably more resistant to TNF than C57BL/6 mice. The resistance proved to be dominant since (C57BL/6 x DBA/2)F1 mice were also resistant. Using BXD recombinant inbred mice and a dose of TNF lethal for C57BL/6 but not for DBA/2 mice, we found that the resistance to TNF links to loci coding for corticosteroid-binding globulin (Cbg), alpha1-protease inhibitor (Spi1), contrapsin (Spi2) and the contrapsin-regulating gene Spi2r that form a gene cluster on chromosome 12. Quantitative trait-loci analysis of TNF-induced induction of IL-6 and of hypothermia also points to the importance of this locus (P < 0.0002 and P = 0.017, respectively), more particularly the Cbg and Spi2 loci, in the resistance to TNF. We propose to name the locus "TNF protection locus." The data suggest that endogenous protease inhibitors and/or glucocorticoids play a significant role in the attenuation of TNF-induced lethal shock. This study also demonstrates that loci affecting important biological responses can be identified with very high resolution using recombinant inbred mice.
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PMID:Identification of a locus on distal mouse chromosome 12 that controls resistance to tumor necrosis factor-induced lethal shock. 1004 82

To assess the adequacy of gastrointestinal mucosal perfusion perioperatively, the gastric intramucosal PCO2 (PiCO2) was monitored in ten patients undergoing elective coronary artery bypass grafting operation. Extracorporeal circulation was performed with mild hypothermia (temperature between 30 degrees C and 32 degrees C) and nonpulsatile flow. Plasma levels of interleukin-6 and endothelin-1 remained elevated up to twelve hours after surgery. The PiCO2 using the ion-sensitive field effect transistor (ISFET) sensor, attached to the tip of a nasogastric tube, increased significantly to 64 +/- 9 mmHg (mean +/- SD) at 6th postoperative hour from a baseline value of 48 +/- 7 mmHg. A similar trend was observed in PiCO2 as measured by capnographic gas tonometry. Although there was a close correlation between these two techniques (r2 = 0.4923), values with ISFET sensor were significantly higher (11-16 mmHg) than those by capnographic gas tonometry. Gastrointestinal mucosal ischemia, probably related to systemic inflammatory response, was observed during the immediate postoperative period. The PiCO2, measured directly and continuously with ISFET sensor, may be a more sensitive indicator compared with capnographic gas tonometry in evaluating the development of gastrointestinal mucosal injury.
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PMID:[Gastrointestinal ischemia in patients undergoing coronary artery bypass surgery--comparison of two methods for gastric intramucosal PCO2 monitoring]. 1040 9

The systemic inflammatory response to cardiopulmonary bypass (CPB) is associated with increased production of cytokines. This systemic inflammatory response characterized by the activation of interleukin-6 (IL-6) and interleukin-8 (IL-8) during and after CPB is well documented. A prospective, randomized, double-blind study was performed so as to understand the effects of low-dose methyl prednisolone sodium succinate (MPSS) on the circulating levels of serum cytokines and clinical outcome. Twenty patients were randomly divided into two groups on the basis of the administration of low-dose (1 mg/kg) MPSS (n = 10) and placebo (n = 10) into the pump prime solution. All patients were scheduled to undergo a primary elective coronary artery bypass grafting operation. Patients receiving concurrent corticosteroids, salicylates, dipyridamol or anticoagulants were excluded from the study. Other exclusion criteria were concurrent chronic obstructive pulmonary disease, chronic renal failure, insulin-dependent diabetes, congestive cardiac failure, peptic ulcer history, prior cardiac operations, recent (in a one-month period) myocardial infarction and steroid dependency. Mild systemic hypothermia (30-32 degrees C, rectal) was assured during the CPB. Four blood samples were drawn from the radial artery catheter immediately before starting CPB (T1), following protamine administration (T2) and at 24 (T3) and 48 h (T4) after completion of CPB. In each sample, creatine kinase-myocardial band (CK-MB), white blood cell (WBC), IL-6 and IL-8 levels were measured. IL-6 and IL-8 concentrations were measured by enzyme immunoassay and enzyme-linked immunoabsorbant assay methods. Serum IL-6 T2 and serum IL-6 T3 levels were significantly higher than IL-6 T1 levels in both groups (p < 0.001) and (p < 0.01), and there was no significant elevation in serum IL-8 levels in either group. Serum IL-6 levels were significantly higher in the placebo group than in the MPSS group at T3 (p < 0.009). There was no significant difference in CK-MB T1 levels between the groups. Although there was no significant difference between CK-MB T1 and T2 levels in the MPSS group, the CK-MB T2 and CK-MB T3 levels were significantly higher than T1 levels in the placebo group (p < 0.001) and (p < 0.05). There was significant elevation of WBC levels at T2 and T3 in both groups without notable difference between the groups (p < 0.05). This study has shown that low-dose MPSS suppresses CPB-induced inflammatory response. Further clinical studies (on larger and higher risk groups) may reveal more information on relations between morbidity and cytokine levels which may have some predictive value on clinical outcome following CPB.
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PMID:Effect of low-dose methyl prednisolone on serum cytokine levels following extracorporeal circulation. 1041 Dec 50

Oral exposure to chlorpyrifos (CHP) in the rat results in an initial hypothermic response followed by a delayed fever. Fever from infection is mediated by the release of cytokines, including interleukin-6 (IL-6) and tumor necrosis factor (TNF alpha). This study determined if the CHP-induced fever involves cytokine-mediated mechanisms similar to that of infectious fevers. Long-Evans rats were gavaged with the corn oil vehicle or CHP (10-50 mg/kg). The rats were euthanized and blood collected at various times that corresponded with the hypothermic and febrile effects of CHP. Plasma IL-6, TNF alpha, cholinesterase activity (ChE), total iron, unsaturated iron binding capacity (UIBC), and zinc were measured. ChE activity was reduced by approximately 50% 4 h after CHP. There was no effect of CHP on IL-6 when measured during the period of CHP-induced hypothermia or fever. TNF alpha levels nearly doubled in female rats 48 h after 25 mg/kg CHP. The changes in plasma cytokine levels following CHP were relatively small when compared to > 1000-fold increase in IL-6 and > 10-fold rise in TNF alpha following lipopolysaccharide (E. coli; 50 microg/kg; i.p.)-induced fever. This does not preclude a role of cytokines in CHP-induced fever. Nonetheless, the data suggest that the delayed fever from CHP is unique, involving mechanisms other than TNF alpha and IL-6 release into the circulation characteristic of infectious fevers.
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PMID:Are circulating cytokines interleukin-6 and tumor necrosis factor alpha involved in chlorpyrifos-induced fever? 1041 84

Female C57BL/6 mice were decapitated and their brains were removed and cultured at either 37 or 33 degrees C for 48 h to investigate whether or not moderate hypothermia alters the cytokine reactions in the ischemic brain. The interleukin-6 and interleukin-1alpha levels in the culture media were significantly elevated in a time-dependent manner. The interleukin-6 levels after the incubation at 33 degrees C were significantly lower than those at 37 degrees C. The interleukin-1alpha levels at 33 degrees C were significantly higher than those at 37 degrees C. The interleukin-1alpha levels incubated with interleukin-6 antibody were significantly higher than those without IL-6 antibody. At 37 degrees C, the mRNA expression of interleukin-6 was observed from 2 to 48 h after incubation, but the same expression of interleukin-1alpha was only detected until 12 h. Accordingly, the ischemic brain incubated at 33 degrees C showed a decreased interleukin-6 production in comparison with that at 37 degrees C and the level of interleukin-6 showed negative feedback for the production of interleukin-1alpha. The temperature should, therefore, be carefully considered when evaluating the cytokine reaction for cerebral ischemia.
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PMID:Moderate hypothermia alters interleukin-6 and interleukin-1alpha reactions in ischemic brain in mice. 1194 85


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