Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While the production of tumor necrosis factor (TNF) and interleukin-6 (IL-6) in septic shock and other inflammatory states is well established, the role of interleukin-8 (IL-8), a recently described neutrophil chemoattractant and activator, has yet to be fully elucidated. Using lipopolysaccharide (LPS)-stimulated human whole blood as an ex vivo model of sepsis, the kinetics of messenger RNA (mRNA) up-regulation and protein release of these cytokines were examined. Two waves of cytokine gene activation were documented. TNF and IL-6 were induced in the first wave with mRNA levels peaking between 2-4 hours and then rapidly declining. TNF and IL-6 protein peaked at 4-6 hours and then stabilized. IL-8 mRNA and protein were induced in the first wave, reached a plateau between 6-12 hours, and rose again in a second wave which continued to escalate until the end of the 24 hour study. These data demonstrate the complex patterns of cytokine gene expression and suggest that production of early mediators may augment continued expression of IL-8 to recruit and retain neutrophils at a site of inflammation.
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PMID:Kinetics of TNF, IL-6, and IL-8 gene expression in LPS-stimulated human whole blood. 198 98

Sepsis results in muscle catabolism and peripheral release of amino acids with a concomitant uptake of amino acids in liver and acute-phase protein synthesis. In addition, there appears to be a cytokine-induced process that blocks muscle amino acid uptake in sepsis, further diverting amino acids from the periphery to the liver. In this article, evidence that cytokines and glucocorticoids play an important role in the regulation of hepatic and muscle protein metabolism during sepsis is presented.
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PMID:Cytokines and glucocorticoids in the regulation of the "hepato-skeletal muscle axis" in sepsis. 199 Aug 81

Using a model of sepsis induced by parenteral challenge of mice with bacterial lipopolysaccharide (LPS), the authors analyzed the in vivo expression of interleukin-1 (IL-1) alpha,beta and tumor necrosis factor (TNF). Both TNF and IL-1 alpha,beta were detected in hepatic sinusoidal macrophages (Kupffer cells), immunohistochemically. Kinetic analysis showed a clear sequence of synthesis. Tumor necrosis factor was produced first, reaching maximal expression at 1 hour after LPS challenge, then rapidly disappeared. IL-1 beta followed, reaching maximal expression at 2 to 3 hours, then dropped off by 6 hours. Interleukin-1 alpha expression reached a peak at 6 hours and had disappeared by 18 hours. Analysis of serum bioactivity also revealed sequential expression that correlated with immunohistochemical findings. Tumor necrosis factor was maximal at 1 hour and IL-1 at 6 hours. The IL-1 bioactivity was not due to interleukin-6 (IL-6), as this was depleted from specimens by immunoabsorption. Also IL-6 bioactivity reached maximal levels at 3 hours, earlier than IL-1. Pretreatment with 4 mg/kg dexamethasone significantly decreased Kupffer cell expression of TNF and IL-1 alpha (about 80% and 60% suppression, respectively) but had less effect on IL-1 beta expression (about 30% suppression). Accordingly, serum levels of TNF were suppressed by 75% while serum IL-1 was decreased by 39%, indicating differential sensitivity of these cytokines to glucocorticoids. Endogenous corticosteroid levels increased as TNF levels decreased, supporting the contention that glucocorticoids regulate TNF synthesis. In contrast, IL-1 levels rose concurrently with corticosterone. These data indicate a sequential activation of cytokine gene expression in vivo, which may be critical to the cascade of events leading to septic shock, and provide evidence that Kupffer cells are a major source of cytokines in endotoxemia. Finally, the differential sensitivity of cytokine expression to glucocorticoids may in part explain the inadequacy of the latter in the treatment of sepsis.
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PMID:In vivo biologic and immunohistochemical analysis of interleukin-1 alpha, beta and tumor necrosis factor during experimental endotoxemia. Kinetics, Kupffer cell expression, and glucocorticoid effects. 199 64

The clinical and immune modulatory effects of interleukin-2 (IL-2) and interferon (INF) alfa-2a were examined in a phase II study in patients with metastatic renal cell carcinoma (six patients) and melanoma (eight patients). Treatment consisted in IL-2 3 MU/m2 continuous infusion days 1-4 and INF alfa-2a 6 MU/m2 subcutaneously day 1 and 4, both given on alternate weeks. Tumour response was assessed after four cycles of treatment or earlier, if necessary. Patients with stable disease or response were to be continued for another nine cycles or up to disease progression. The 14 patients received a total of 60 cycles of treatment. Major toxicities (WHO Grade III/IV) were fever, capillary leak syndrome with hypotension, nausea and vomiting, erythema with pruritus, leuco- and thrombopenia and sepsis with staphylococcus aureus. Five of 14 patients (36%) developed a self limiting autoimmune thyroiditis with HLA-DR expression on thyrocytes. Long term treatment toxicity was moderate with an average weight loss of 5% and an average fall in Karnofsky index of 10% compared to baseline. No responses were seen in renal cell carcinoma, two patients with melanoma had a partial and two a minor response with a duration of 1-7 months. Serial measurements of immune modulatory parameters showed a functional response to treatment with an increase of NK- and LAK-activity during the first two cycles, followed by a plateau and decrease during the third and fourth cycles. These findings were paralleled by a successive decline in treatment induced INF gamma response. These findings suggest, that alternative weekly treatment with IL-2 and INF alfa-2a results in an exhaustion of lytic capacity of NK- and LAK-cells and an attenuation of secondary cytokine release.
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PMID:Clinical and immune modulatory effects of alternative weekly interleukin-2 and interferon alfa-2a in patients with advanced renal cell carcinoma and melanoma. 199 8

The purpose of the study was to evaluate the role of tumor necrosis factor alpha (TNF alpha) in the pathogenesis of acute lung injury in critically ill patients. An immunoradiometric assay with an upper normal limit of 9 pg/ml was used to measure plasma TNF alpha levels (pl-TNF alpha) in 34 patients with adult respiratory distress syndrome (ARDS) and in 16 patients in whom, despite the presence of risk factors, ARDS did not develop. Pl-TNF alpha was elevated in 76% of the patients with ARDS (71 +/- 104 pg/ml) and in 48% of the at-risk patients (47 +/- 73 pg/ml); the difference between the two groups was not statistically significant. In 13 patients studied serially from the onset (Day 0) to the fifth day of ARDS, the peak pl-TNF alpha occurred later than Day 0 in seven subjects. Although the highest pl-TNF alpha levels were found in septic patients, moderately elevated values were also observed in 56% of nonseptic subjects. We conclude that plasma TNF alpha level is not a marker of ARDS but rather of shock and sepsis. These results do not exclude a pathogenic role of TNF alpha in acute lung injury since this cytokine could be produced and exert its effects within the lungs. The large incidence of abnormally high could be produced and exert its effects within the lungs. The large incidence of abnormally high plasma TNF alpha levels raises important questions on the role of this toxic cytokine in other disorders occurring in critically ill patients.
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PMID:Plasma levels of tumor necrosis factor in the adult respiratory distress syndrome. 200 Oct 71

Much effort has been directed toward elucidating the host response to sepsis and inflammation, resulting in the definition of a cascade of endogenous mediators that direct metabolic and immunological responses. Here we report that IL-8, a novel cytokine produced by a variety of cells in vitro in response to stimulation with bacterial LPS and the proinflammatory cytokines, appears in the circulation of primates in vivo during septic shock, sublethal endotoxemia, and after the administration of IL-1 alpha. The magnitude of the IL-8 response correlates with the severity of the insult, and levels of IL-8 peak relatively late, after those of TNF-alpha and IL-1 beta, and simultaneously with those of IL-6. IL-8 has been primarily defined as a selective activator and chemoattractant of neutrophils, and we demonstrate that after LPS or IL-1 alpha infusion, circulating neutrophil numbers rapidly recover from an initial neutropenia while IL-8 concentrations are maximal, supporting the hypothesis that IL-8 influences circulating leukocyte populations in vivo. We conclude that IL-8 is another participant in the cytokine cascade elicited by sepsis and inflammation and, as such, may play a significant role in host defense and disease.
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PMID:IL-8 in septic shock, endotoxemia, and after IL-1 administration. 202 76

Based on the hypothesis that tumor necrosis factor (TNF) causes the lethality of gram-negative sepsis and previous work of tolerance to the lethal effects of TNF induced by repetitive exposure to sublethal intraperitoneal doses of human recombinant (r) TNF, we studied the protective role of a single sublethal intravenous dose of either rTNF (100 micrograms/kg) or recombinant interleukin-1 (rIL-1; 10(5) units/kg) or both before a subsequent lethal intravenous dose of rTNF (800 to 1000 micrograms/kg) in C3H/HEN mice. Mice were treated with a single intravenous dose of saline, rTNF, rIL-1 or both cytokines and challenged within 2 hours to 10 days with a lethal dose of rTNF. Mice treated with rTNF showed significant protection against the lethal effects of TNF when the treatment dose was given only 2 hours before the lethal dose, but maximal protection required a 24-hour interval and lasted as long as 8 days. The treatment dose of rTNF was toxic, and it resulted in occasional treatment deaths. Mice treated with rIL-1 showed maximal protection when treatment was given only 2 hours before challenge and protection lasted for 8 days. No toxicity was apparent secondary to IL-1 treatment. The combination of rIL-1 and rTNF was not as effective as either cytokine alone. The results suggest that rTNF or rIL-1 may be clinically useful in the prevention and treatment of sepsis lethality by the induction of tolerance to the lethal effects of TNF. The more promising cytokine appears to be rIL-1 because it has less toxicity and more rapid induction of full therapeutic effectiveness.
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PMID:Tumor necrosis factor and interleukin-1 protection against the lethal effects of tumor necrosis factor. 204 87

Recent studies in alcoholic hepatitis have proposed a role for the cytokine tumour necrosis factor-alpha (TNF-alpha) a mediator of endotoxic shock in sepsis. In this study plasma levels of the closely related cytokine interleukin-6 (IL-6) were assayed in 96 samples from 58 patients with severe alcoholic hepatitis, and 69 patients in control groups (21 normal, 10 alcoholic without liver disease, 10 inactive alcoholic cirrhosis, 18 chronic liver disease, 10 chronic renal failure). Plasma IL-6 levels were markedly elevated in patients with alcoholic hepatitis when compared with all control groups (P less than 0.001). IL-6 levels were higher in patients who died (P = 0.04) and correlated with the features of severe disease including: increased grade of encephalopathy, increased neutrophil count, increased prothrombin ratio, hypotension, increased serum creatinine and increased serum bilirubin. Surprisingly, no correlation was found between levels of plasma IL-6 and plasma TNF-alpha or endotoxin, or the presence of infection; an inverse correlation was found between plasma IL-6 and serum globulins. These findings provide further evidence that the IL-6/TNF cytokine system is activated in severe alcoholic hepatitis and may mediate hepatic or extra-hepatic tissue damage.
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PMID:Elevated plasma interleukin-6 and increased severity and mortality in alcoholic hepatitis. 204 24

Tumor necrosis factor-alpha (TNF alpha) and interleukin-1 alpha (IL-1 alpha) are pluripotent cytokines mediating the host response to sepsis, injury, and cancer. Animals can be protected from the lethal effects of TNF alpha by repeated administration of sublethal doses, but the mechanism of this effect is not known. Human foreskin fibroblasts (FS4 cells), which rapidly elaborate interleukin-6 (IL-6) when stimulated with TNF alpha or IL-1 alpha, were grown in culture as confluent monolayers and their secretion of IL-6 was quantitated using the murine B9-hybridoma bioassay against an external reference of human recombinant IL-6 (Genetics Institute). When FS4 cells were incubated with human recombinant TNF alpha (50 ng/ml; Cetus) or recombinant IL-1 alpha (30 pg/ml; Genzyme) a rapid increase in IL-6 production was measured over control, rising to IL-6 levels of 71.7 +/- 5.9 units/ml with TNF alpha and 54.0 +/- 1.2 units/ml with IL-1 alpha after 7.5 hr incubation. FS4 cells which were exposed to cytokine, rinsed, and then reexposed to cytokine 24 hr later produced significantly less IL-6 [38.1 +/- 2.8 units/ml with second exposure to TNF alpha (P less than 0.05), and 18.3 +/- 1.9 units/ml with second exposure to IL-1 alpha (P less than 0.01)]. Successive daily exposure to TNF alpha or IL-1 alpha caused a further stepwise diminution of IL-6 secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Decreased IL-6 secretion by fibroblasts following repeated doses of TNF alpha or IL-1 alpha: post-transcriptional gene regulation. 206 55

Although antibiotics have reduced mortality, the most recent clinical trials in sepsis and meningitis have been directed at the host inflammatory response in an attempt to improve outcome. Endotoxin, cell wall constituents and toxins are potent inducers of small molecular weight proteins (cytokines) from a variety of host cells. Several lines of investigation have implicated tumor necrosis factor-alpha (TNF-alpha) as a cytokine mediator of sepsis and septic shock. A recent study has been able to measure plasma TNF-alpha concentrations in patients with meningococcemia and demonstrated a correlation with prognostic groups related to mortality. Therefore, TNF-alpha, probably through its effects on other mediators, has an effect in sepsis. New speculation regarding morbidity in bacterial meningitis focuses on cytokine activity in the central nervous system. Cerebrospinal fluid (CSF) from experimental animals with meningitis contains increased amounts of interleukin-1 beta (IL-1 beta) and TNF alpha. These IL-1 beta levels correlated directly with duration of fever and neurological sequelae. Children with Haemophilus influenzae, type b meningitis treated with dexamethasone had significantly reduced levels of CSF IL-1 beta compared to placebo-treated controls.
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PMID:The immunology of sepsis and meningitis--cytokine biology. 209 Dec 57


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