High levels of serum interleukin-10 and tumor necrosis factor-alpha are associated with fatality in fulminant hepatitis

Serum pro- and anti-inflammatory mediators in patients with acute liver diseases were assessed to clarify the clinical significance of these measurements in relation to disease severity. Concentrations of circulating tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-10, IL-12, and soluble TNF receptors (sTNFR) p55 and p75 were measured at admission in patients with fulminant hepatitis (FH; n=19), severe acute hepatitis (AHS, n=15), or acute hepatitis (AH, n=7). Serum concentrations of TNF-alpha, IL-10, and sTNFR-55 were significantly higher in patients with FH than in those with AHS (P<.05, <.05, and <.01, respectively) or AH (P<.05). Serum IL-10 and TNF-alpha levels were higher in patients who died of FH (n=13) than in FH survivors (n=6; P<.05). The ratios between TNF-alpha and IL-10 and sTNFR-55 or sTNFR-75 were not valuable in predicting mortality and disease severity. However, both proinflammatory cytokine TNF-alpha and anti-inflammatory cytokine IL-10 levels at admission were associated with fatal outcome among patients with FH.     

老年急性心肌梗死患者肿瘤坏死因子-α和白细胞介素-10的变化及辛伐他汀的干预作用

目的　探讨老年人急性心肌梗死 (AMI)患者外周循环肿瘤坏死因子 α(TNF α)和白细胞介素 10 (IL 10 )的变化及辛伐他汀对TNF α和IL 10的作用。方法　测定 39例老年AMI患者 (AMI组 )、2 0例老年陈旧性心肌梗死 (OMI)患者 (OMI组 )及 2 0例正常老年人 (正常人组 )血清TNF α和IL 10浓度。 39例AMI患者入院后随机分为辛伐他汀组和对照组 ,治疗前、治疗后 1周和 6周测定血清TNF α和IL 10浓度。结果　AMI组TNF α、IL 10水平明显高于OMI组 ;OMI组TNF α水平明显高于正常人组 ;正常人组血清IL 10未检测到。辛伐他汀组和对照组经治疗后 1周、6周TNF α水平均显著下降 ,6周后辛伐他汀组TNF α水平显著低于对照组。辛伐他汀组和对照组IL 10水平 6周后均显著降低 ,但两组差异无显著性意义。结论　辛伐他汀具有降低AMI患者血清TNF α水平的作用 ,对IL 10水平无影响     

Balance between plasma levels of tumor necrosis factor-alpha and interleukin-10 in rheumatic mitral stenosis

The study population consisted of 16 patients with rheumatic mitral stenosis undergoing percutaneous transluminal mitral valvuloplasty (group 1). The plasma levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) in the femoral vein and the right and left atria before valvuloplasty were determined by ELISA. Additionally, we measured plasma concentrations of TNF-alpha and IL-10 in the venous blood obtained from 19 control patients, including 12 healthy volunteers in sinus rhythm (group 2) and 7 patients in permanent lone atrial fibrillation (group 3). The venous plasma levels of TNF-alpha were significantly elevated in group 1 patients compared with group 2 patients (p < 0.002). Correlation analysis demonstrated that there was a significantly direct relationship between the plasma TNF-alpha and IL-10 concentrations in the left atrial, right atrial and peripheral venous blood (p < 0.008, r = 0.640; p < 0.04, r = 0.538; p< 0.03, r = 0.571, respectively). In conclusion, the plasma concentrations of TNF-alpha of patients with rheumatic mitral stenosis were significantly higher than those of healthy volunteers. In addition, there was a significantly direct relationship between the soluble TNF-alpha and IL-10 concentrations in the atrial and peripheral venous blood, indicating a balance between circulating TNF-alpha and IL-10 levels in patients with rheumatic mitral stenosis.     

Increased plasma group II phospholipase A(2) concentrations in patients with acute myocardial infarction: correlation with tumor necrosis factor-alpha

AIMS: Group II phospholipase A(2) (PLA(2)) is thought to play an important role in inflammation and tissue injury. It has been suggested that the inflammatory process is important in the setting and progression of myocardial ischemia or reperfusion. We measured plasma PLA(2) as well as inflammatory cytokines in patients in the acute stage of myocardial infarction. METHODS AND RESULTS: In 48 patients with acute myocardial infarction, blood samples were taken to measure plasma PLA(2), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) 36-48 h after onset. Serial changes in plasma PLA(2) were also examined in 15 consecutive patients in this group. Plasma PLA(2) levels were significantly higher in complicated patients (Killip's class > or = II) than in uncomplicated patients (Killip's class = I) (35.9 +/- 11.9 vs. 5.3 +/- 1.1 ng/ml, p < 0.01). Plasma PLA(2) concentrations increased gradually over time during the first 3 days and at 36-48 h after onset were correlated with left-ventricular ejection fraction on admission (r = -0.42, p < 0.01), and with plasma TNF-alpha (r = 0.39, p < 0.01), but not with IL-1 beta. CONCLUSION: Plasma PLA(2) concentrations rose during the acute stage of myocardial infarction, especially in severe cases mainly with heart failure. TNF-alpha may be associated with PLA(2)activity as a potent stimulator in vivo.     

Increased ratio of tumor necrosis factor-alpha to interleukin-10 production is associated with Schistosoma haematobium-induced urinary-tract morbidity

Bladder and kidney disease, which affect approximately 25%-30% of subjects infected with Schistosoma haematobium, are mediated by T cell-dependent granulomatous responses to schistosome eggs. To determine why only some infected subjects develop disease, we examined the hypothesis that infected Kenyan subjects with ultrasound-detected urinary-tract morbidity (n=49) had dysregulated cytokine production leading to enhanced granulomatous responses, compared with subjects of similar age and intensity of infection without morbidity (n=100). Peripheral blood mononuclear cells from subjects with morbidity produced 8-fold greater levels of egg antigen-driven tumor necrosis factor (TNF)-alpha and had a 99-fold greater mean TNF-alpha:interleukin (IL)-10 ratio, compared with subjects without disease. No differences in cytokine response to non-egg-derived schistosome antigens were observed between groups. Subjects with morbidity had increased TNF-alpha production in response to endotoxin, suggesting an innate hyperresponsiveness. These results indicate that increased TNF-alpha production, relative to that of IL-10, is associated with developing bladder-wall morbidity with S. haematobium infection.     

High circulating levels of tumor necrosis factor-alpha in centenarians are not associated with increased production in T lymphocytes

BACKGROUND: Aging is characterized by increased inflammatory activity reflected by increased plasma levels of proinflammatory cytokines, concomitant with an altered cytokine profile of T lymphocytes. High plasma levels of tumor necrosis factor (TNF)-alpha are strongly associated with morbidity and mortality in elderly humans. However, the cellular source and mechanisms for the increased circulating TNF-alpha levels are unknown. OBJECTIVE: The aim of the present study was to investigate if high plasma levels of TNF-alpha are associated with increased production of TNF-alpha by T lymphocytes in elderly humans. METHODS: TNF-alpha production by CD4+ and CD8+ T lymphocytes was measured by flow cytometry following stimulation with phorbol 12-myristate 13-acetate and ionomycin in 28 young controls, 14, 81-year-olds and 25 centenarians. RESULTS: Plasma levels of TNF-alpha increased with increasing age. An increased percentage and number of T lymphocytes from the 81 year olds expressed TNF-alpha, whereas centenarians did not show this altered TNF-alpha secretion profile. CONCLUSION: T cells may contribute to the elevated levels of plasma TNF-alpha in healthy elderly subjects, whereas other mechanisms are responsible in very old individuals.     

Polymorphisms of interleukin-10 and tumour necrosis factor-alpha genes are associated with newly diagnosed and recurrent pulmonary tuberculosis

BACKGROUND AND OBJECTIVES: The genetic determinants for developing TB or having recurrent TB are unknown. The present study investigated the relationship between susceptibility to tuberculosis and human tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 genes (IL-10). METHODS: A case-control study was conducted using two groups of cases--newly diagnosed TB (N-TB) and recurrent TB (R-TB)--and a control group. RESULTS: One hundred and seventeen healthy controls, 80 newly diagnosed TB patients and 65 patients with recurrent TB were enrolled. There was no significant difference in the TNF-alpha-308 G/A genotype between the TB patient groups and the controls. The IL-10 -1082A alleles were markedly over-represented among the TB patient groups compared with the control subjects, however, there was no significant difference in the IL-10 genotype frequency between the N-TB and R-TB patient groups. CONCLUSION: The -1082A allele of the IL-10 gene may be important in determining susceptibility to TB, however, the -308 allele of the TNF-alpha gene does not affect differential TB susceptibility.     

Effect of interleukin-10 on the production of tumor necrosis factor-alpha by peripheral blood mononuclear cells from patients with chronic heart failure

Chronic heart failure (HF) is a state of inflammatory immune activation characterized by elevated circulating levels of tumor necrosis factor-alpha (TNF-alpha). Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that inhibits TNF-alpha production and lessens endotoxin bioactivity. It is not known whether IL-10 reduces lipopolysaccharide (LPS) stimulated TNF-alpha production of peripheral blood mononuclear cells (PBMCs) from patients with chronic HF. PBMCs were isolated from 15 patients with chronic HF (New York Heart Association functional class 3.0 +/- 0.2, left ventricular ejection fraction 30 +/- 2%, peak oxygen consumption 18.1 +/- 0.8 ml/kg/min) and 15 healthy control subjects and stimulated with 1 and 10 ng/ml LPS for 24 hours with or without prior addition of IL-10 (10 ng/ml). TNF-alpha was quantified in cell-free supernatants by an enzyme-linked immunosorbent assay. TNF-alpha, soluble TNF receptors, IL-10, and LPS were quantified in plasma. LPS stimulated TNF-alpha production was highest in those patients in New York Heart Association class II (p <0.01 vs New York Heart Association class III and IV, p <0.001 vs control subjects). IL-10 reduced PBMC TNF-alpha production in all stimulated samples at 1 and 10 ng/ml LPS (mean reduction 43% at 1 ng/ml, p <0.01 and 55% at 10 ng/ml, p <0.0001). The percentage reduction in TNF-alpha release did not differ significantly between patients and control subjects or with respect to severity of chronic HF or baseline immune parameters. Independently of clinical severity, IL-10 profoundly inhibits TNF-alpha release from PBMCs isolated from patients with chronic HF. IL-10 is, therefore, a potential therapy for use in chronic HF associated with inflammatory immune activation.     

Circulating interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and soluble ICAM-1 in patients with chronic stable angina and myocardial infarction

The changes in serum concentrations of cytokines such as interleukin-1 (IL-1) beta, interleukin-6 (IL-6), tumor necrosis factor (TNF) alpha and a soluble-intercellular adhesion molecule (sICAM-1) has been investigated in patients with stable angina and acute myocardial infarction. Thirty-four patients with stable angina (SA), 15 with acute myocardial infarction (AMI), and 20 subjects in the control (C) group were included in the study. The mean serum concentrations of sICAM-1, IL-1-beta, IL-6, and TNF-alpha differed significantly among the three groups. Serum concentrations of IL-1 beta, sICAM-1, and TNF-alpha were comparable in the AMI and SA groups and higher than those found in the C group (p < 0.001). The serum concentration of IL-6 was more than twice as high in the AMI group as compared to the other two groups (p < 0.001). The mean serum concentrations of IL-1 beta, TNF-alpha, and IL-6 were comparable in the AMI and SA groups and higher than in the C group.     

Polymorphisms of tumor necrosis factor-alpha and interleukin-10 genes in Japanese patients with idiopathic dilated cardiomyopathy

Various cytokines play important roles in the pathogenesis of congestive heart failure. TNF-alpha is one of the pro-inflammatory cytokines, and IL-10 has anti-inflammatory actions. The -308 (G / A) polymorphism of the TNF-alpha gene (TNFA1 and A2) and the single base -1082 (G / A) polymorphism of the IL-10 gene (IL-10 1*G and 1*A) have been identified as causing alterations to the in vivo production of TNF-alpha and IL-10, respectively. We examined TNF-alpha and IL-10 gene polymorphisms using a polymerase chain reaction-restriction fragment length polymorphism technique in 48 Japanese patients with idiopathic dilated cardiomyopathy. The frequency of these polymorphisms was compared with 50 healthy Japanese. The clinical courses, such as disease onset, left ventricular function, progression during the follow up period and hospitalization from congestive heart failure, were also analyzed. Serum TNF-alpha levels were measured using an enzyme-linked immunosorbent assay (ELISA) technique in the patients with idiopathic dilated cardiomyopathy to reveal the correlation with genotypes. Patients with ischemic cardiomyopathy or other secondary cardiomyopathies were excluded from this study. The allele frequency of TNFA2 in idiopathic dilated cardiomyopathy was significantly higher than that of the healthy group (13.5% and 3.0%, respectively, p = 0.0084). There was no difference in the allele frequency of the IL-10 gene between the two groups. Polymorphism of the TNFA2 gene was not associated with the clinical course. Serum TNF-alpha levels were elevated in the patient group compared with the healthy group. There were no differences in serum TNF-alpha levels between the patients with TNFA1 and those with TNFA2. In conclusion, the TNFA2 allele may be linked to the pathogenesis of idiopathic dilated cardiomyopathy in Japanese patients.     

Prognostic value of cytokine concentrations (tumor necrosis factor-alpha, interleukin-6, and interleukin-10) and clinical parameters in severe melioidosis

Raised serum concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, or IL-10 are associated with mortality in patients with sepsis, but it is not known whether elevated cytokine levels are independently predictive of mortality. Cytokine assays (TNF-alpha, IL-6, and IL-10) were performed on admission plasma samples from 172 adult Thai patients with severe melioidosis. Mortality was 31.4%. APACHE II score; septicemia; plasma lactate; TNF-alpha, IL-6, and IL-10 concentrations; and IL-10/TNF-alpha and IL-6/IL-10 ratios were each associated with outcome (P相似文献   

Accumulation of LDL in rat arteries is associated with activation of tumor necrosis factor-alpha expression

Activation of vascular inflammation in response to hyperlipidemia is believed to play an important role during the early stages of atherogenesis. We demonstrate here that exposure of cultured, rat aortic smooth muscle cells to low density lipoprotein (LDL) stimulated tumor necrosis factor-alpha (TNF-alpha) mRNA and protein expression. Oxidative modification of LDL resulted in a reduction of this stimulatory effect. To analyze whether a similar response also occurs in vivo, we used a recently developed model in which the effects of a rapid accumulation of human LDL in rat arteries can be studied. As previously reported, epitopes specific for human apolipoprotein B began to accumulate in the aorta within 2 to 6 hours after injection of 6 mg of human LDL. This was followed by expression of oxidized LDL-specific epitopes after 12 hours. There was no vascular expression of TNF-alpha at baseline or in phosphate-buffered saline-injected control rats. However, 24 hours after injection of native LDL, there was a marked induction of TNF-alpha mRNA and immunoreactivity in the aorta and other large arteries, whereas injection of oxidized LDL was without effect in this respect. Preincubation of LDL with the antioxidant probucol before injection markedly decreased the expression of TNF-alpha immunoreactivity. The present findings support the notion that LDL may activate arterial expression of TNF-alpha and suggest 1 possible mechanism for the inflammatory response in the early stages of atherosclerosis. The role of LDL oxidation in this process remains to be fully elucidated.     

多聚ADP核糖聚合酶-1与糖尿病血管并发症

多聚ADP核糖聚合酶（PARP）1是PARP核酶家族主要成员,分布广泛,是机体修复DNA损伤的关键酶之一,但其过度激活又会造成细胞的死亡。糖尿病时的氧化应激状态可以造成血管内皮细胞内源性DNA损伤,从而大量激活PARP,进而导致内皮细胞的死亡。这是糖尿病大血管和微血管并发症发生的共同机制。抑制PARP可有效防止内皮细胞的损伤,预防甚至逆转糖尿病血管并发症,对PARP的干预可能成为防治糖尿病血管并发症的一个新靶点。     

Evaluation of the poly(ADP-ribose) polymerase gene in human stroke

Nitric oxide (NO) and its reactant product, peroxynitrite, have been implied to mediate neuronal damage following cerebral ischemia. However, the cellular targets of these compounds remain unclear. Studies using poly(ADP-ribose) polymerase (PARP) inhibitors and PARP knock-out mice have recently demonstrated that excessive activation of this nuclear enzyme plays an important role in NO-induced neurotoxicity. To evaluate the relevance of this plausible candidate gene to human stroke, we undertook a case-control study in Japanese. Participants comprised 213 cerebral infarction cases and 374 age- and sex-matched controls. As a primary investigation, we screened polymorphic sites of the PARP gene, and newly identified a total of four polymorphisms in 1230-bp 5'-flanking sequence. None of them were, however, located on the known promoter components of the gene. Two bi-allelic polymorphisms selected and a CA-repeat polymorphism were subsequently characterized in the case-control study, but none were significantly associated with cerebral infarction in the present study. Our data thus suggest that the tested PARP polymorphisms do not principally contribute to cerebral infarction, although extensive searches would be required to clarify whether the PARP gene plays an important role in the pathogenesis of human stroke.     

Role of poly(ADP-ribose) polymerase in rapid intracellular acidification induced by alkylating DNA damage

In response to high levels of DNA damage, catalytic activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) triggers necrotic death because of rapid consumption of its substrate beta-nicotinamide adenine dinucleotide and consequent depletion of ATP. We examined whether there are other consequences of PARP activation that could contribute to cell death. Here, we show that PARP activation reaction in vitro becomes acidic with release of protons during hydrolysis of beta-nicotinamide adenine dinucleotide. In the cellular context, we show that Molt 3 cells respond to DNA damage by the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) with a dose-dependent acidification within 30 min. Whereas acidification by 0.15 pH units induced by 10 microM MNNG is reversed within 1 h, 100 , microinduced acidification by 0.5-0.6 pH units is persistent up to 7 h. Acidification is a general DNA damage response because H(2)O(2) exposure also acidifies Molt 3 cells, and MNNG causes acidification in Jurkat, U937, or HL-60 leukemia cells and in PARP(+/+) fibroblasts. Acidification is significantly decreased in the presence of PARP inhibitors or in PARP(-/-) fibroblasts, suggesting a major role for PARP activation in acidification. Inhibition of proton export through ATP-dependent Na(+)/H(+) exchanger is another major cause of acidification. Using the pH clamp method to either suppress or introduce changes in cellular pH, we show that brief acidification by 0.5-0.6 pH units may be a negative regulator of apoptosis while permitting necrotic death of cells with extensively damaged DNA.     

Anti-inflammatory cytokine profile in human heart failure: behavior of interleukin-10 in association with tumor necrosis factor-alpha

Proinflammatory cytokines, i.e., tumor necrosis factor-alpha (TNFalpha), participate in the development and the progression of congestive heart failure (CHF). On the other hand, an anti-inflammatory cytokine may neutralize the proinflammatory cytokines of CHF. Interleukin-10 (IL-10) is known to suppress the synthesis of proinflammatory cytokines. IL-10 and the IL-10 receptor system was investigated in comparison with the behavior of TNFalpha in 68 patients with various causes of CHF (mean age: 61 years) and in 31 normal subjects (61 years). The circulating IL-10 level was higher in CHF patients than in normal subjects (p<0.05). The TNFalpha level was higher in CHF patients than in control subjects (p<0.005). The ratio of IL-10 to TNFalpha tended to be higher in control subjects than in patients with CHF (p = 0.09). With lipopolysaccharide treatment, the release of IL-10 was more enhanced from mononuclear leukocyte of patients with CHF than from control subjects (p<0.05). The expression of the IL-10 receptor estimated by flow cytometry of mononuclear leukocytes was higher in the CHF patients than in the normal subjects. The IL-10/IL-10 receptor system was activated, at least partly, to downregulate an excess of TNFalpha in patients with advanced CHF. IL-10 may be an important inherent component of the cytokine network of CHF.