Soluble TNF-alpha and interleukin-6 receptors in the urine of heart failure patients. Their clinical value and relationship with plasma levels

BACKGROUND: Proinflammatory cytokines are important mediators in heart failure (HF). Recently, urinary levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) have been determined. AIMS: The purpose of this study was to measure the urinary levels of TNF-alpha and IL-6 receptors, sTNF-RI, sTNF-RII, sIL-6R, and the relationship with plasma levels and NYHA classes in HF. METHODS: Plasma and urine were collected from 114 HF patients and sTNF-RI, sTNF-RII and sIL-6R (ng/ml) were analyzed. RESULTS: For the whole population, plasma levels of sTNF-RI were 2.1+/-0.1, of sTNF-RII were 5.0+/-0.3 and of sIL-6R were 49.8+/-2.5. Urinary levels were: sTNF-RI, 2.8+/-0.5, r=0.5, p<0.001; sTNF-RII, 12.6+/-2.1, r=0.4, p<0.001; and sIL-6R, 4.2+/-0.4, NS. In NYHA III subjects, we found sTNF-RI, r=0.6, p<0.01, sTNF-RII, r=0.5, p<0.05, and sILR-6, r=0.5, p<0.05. Both plasma TNF receptors and urinary levels of sTNF-RII were higher in patients in a more severe NYHA class (p<0.05). CONCLUSIONS: Urine is a good environment to study sTNF-RI and sTNF-RII, and this fact has diagnostic and prognostic implications. Plasma and urinary levels of TNF receptors showed a fair correlation, which was increased in higher NYHA classes. Plasma and urinary levels of sIL6R showed a good correlation in NYHA III. The TNF receptor levels in urine increased in patients with more severe HF.     

华支睾吸虫病患者细胞因子水平与肝功能关系的研究

目的　探讨华支睾吸虫病患者细胞因子水平与肝功能的关系。　方法　 47例确诊、但未经药物治疗的华支睾吸虫病患者 ,参照Child Pugh肝功能分级法 ,按照评分将其分成A ( 3～ 4分 ) 2 0例、B( 5～ 6分 ) 15例、C( 7～ 9分 )12例等 3组。用放射免疫法及双抗体夹心酶联免疫吸附测定 (ELISA)法 ,检测血清白细胞介素 2 (IL-2 )、可溶性白细胞介素 2受体 (sIL-2R )、白细胞介素 8(IL-8)、肿瘤坏死因子α(TNF-α) ;用全自动生化分析仪检测患者血清总胆红素(TBL)、血清白蛋白 (ALB)、丙氨酸氨基转移酶 (ALT)。并进行统计分析。　结果　华支睾吸虫病患者sIL-2R、IL-8、TNF-α水平明显高于健康人对照组 (P <0.0 5 ,P <0.0 5 ,P <0.0 1) ,而IL 2含量明显减少 (P <0.0 1)。随着患者肝功能受累程度的加重 ,sIL-2R、IL-8、TNF-α含量依次递增 ,IL-2含量依次递减 ,A组和C组间差异具有显著性意义 (P <0.0 5 )。sIL-2R、TNF α含量与其TBL(r =0.3 3 1　P <0.0 5 ,r =0.5 18　P <0.0 1)及ALT (r =0.475　P <0.0 1,r =0.2 85　P <0.0 5 )呈正相关 ,与ALB呈负相关 (r =-0.3 19　P <0.0 5 ,r =-0.665　P <0.0 1)。　结论　华支睾吸虫病患者细胞免疫功能降低 ,血清IL-2、sIL-2R、TNF-α水平与肝功能状态有一定关系。     

Serum interleukin-6, soluble interleukin-6 receptor and soluble gp130 exhibit different patterns of age- and menopause-related changes

Growing evidence suggests that interleukin-6 (IL-6) may play a pathogenetic role in postmenopausal bone loss and in other age-related pathological conditions. In this study, we have examined the age-related changes in the serum levels of IL-6 and the soluble receptors that modulate its biological activity--soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130)--in 220 women (from 25 to 104yr old), including 22 centenarians. Serum IL-6 rose exponentially with age (r=0.74, p<0.0001). The median level of IL-6 increased almost ten-fold with age, from 1.16pg/ml in premenopausal women to 10.27pg/ml in centenarians. Serum sIL-6R and sgp130 showed an increase until the seventh decade and a progressive decrease in older ages (r=0.39, p<0.0001 and r=0.26, p=0.008, respectively). IL-6, sIL-6R and sgp130 were significantly higher in women within 10yr of menopause as compared to premenopausal subjects (1.51 vs. 1.16pg/ml, p=0.012; 41.9 vs. 35.7ng/ml, p=0.002; and 253.4 vs. 230.7ng/ml, p=0.008, respectively). In postmenopausal women, a negative correlation was found between sIL-6R and the lumbar bone mineral density (BMD) (r=-0.28, p=0.002) even after adjusting for age and weight. Furthermore, sIL-6R levels were higher in osteoporotic compared to normal women (47.9 vs. 39.5ng/ml, p=0.001). In conclusion, our results show that the serum levels of IL-6, sIL-6R and sgp130 exhibit different patterns of age- and menopause-related changes, and that the biological activity of IL-6 may be increased with age with potential implications in the age-related diseases such as osteoporosis.     

Diverse effect of inflammatory markers on insulin resistance and insulin-resistance syndrome in the elderly

OBJECTIVES: To evaluate the potential association between different inflammatory markers and insulin resistance (IR), as well as insulin-resistance syndrome (IRS) in a large, population-based study of older, nondiabetic persons. DESIGN: Cross-sectional study. SETTING: Outpatient clinic in Greve in Chianti and Bagno a Ripoli (Italy). PARTICIPANTS: One thousand one hundred forty-six nondiabetic subjects ranging in age from 22 to 104. MEASUREMENTS: Anthropometric measurements; plasma fasting levels of glucose, insulin, and cholesterol (total, high-density lipoprotein, low-density lipoprotein); homeostasis model assessment to estimate degree of insulin resistance; tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), soluble IL-6 receptor (sIL-6R), interleukin receptor antagonist (IL-1ra), and C-reactive protein (CRP) plasma concentrations; diastolic, systolic, and mean arterial blood pressure; and echo-color-Doppler duplex scanning examination of carotid arteries. RESULTS: Insulin resistance correlated with age (r=0.102; P<.001) and plasma levels of TNF-alpha (r=0.082; P=.007), IL-1ra (r=0.147; P<.001), IL-6 (r=0.133; P<.001), sIL-6R (r=-0.156; P<.001), and CRP (r=0.83; P<.001). Subjects in the upper tertile of IR degree were older and had higher serum levels of TNF-alpha, IL-1ra, and IL-6 and lower levels of sIL-6R than subjects in the lowest tertile. Independent of age, sex, body mass index, waist-to-hip ratio, triglycerides, drug intake, diastolic blood pressure, smoking habit, and carotid atherosclerotic plaques, higher IL-6 (t=2.987; P=.003) serum concentrations were associated with higher IR, whereas sIL-6R levels (t=-5.651; P<.001) were associated with lower IR. Furthermore, IL-1ra concentrations (t=2.448; P=.015) were associated with IRS, and higher sIL-6R plasma levels continued to correlate negatively with IRS. CONCLUSION: Different inflammatory markers are associated with a diverse effect on IR and IRS in elderly nondiabetic subjects.     

百草枯中毒患者的IL-6、sIL-6R、sgp130水平及其与患者预后的相关性分析

目的 探讨百草枯中毒患者的IL-6、sIL-6R、sgp130表达水平及其与患者预后的关系.方法 选取2017年1月至2019年7月我院收治的百草枯中毒患者60例作为中毒组,选择同期来我院进行健康体检的志愿者60名为对照组.根据患者的预后情况将中毒组患者分为预后良好组(38例)和预后不良组(22例).比较中毒组患者和对...     

可溶性糖蛋白130与稳定型冠心病患者冠状动脉粥样硬化严重程度之间关系

目的: 评估稳定型冠状动脉疾病（stable coronary artery disease, CAD）患者血清白细胞介素-6（IL-6）、可溶性IL-6受体（sIL-6R）和可溶性糖蛋白130（sgp130）浓度及与冠状动脉粥样硬化严重程度间的关系。方法：纳入2017年1月到2019年1月间于惠州市第六人民医院心内科具有动脉造影适应症疑似冠心病患者89例,根据冠状动脉造影结果将患者分成两组：存在冠状动脉粥样斑块CAD组,即粥样斑块组,共64例;不存在冠状动脉粥样斑块CAD组,即非粥样斑块组,共25例。采用ELISA法检测两组患者血清IL-6、sIL-6R和sgp130浓度,Spearman相关分析sgp130浓度与受累冠脉数目及Gensini评分的相关性,多因素logistic回归分析冠状动脉粥样硬化斑块病变的预测因子。结果： 粥样斑块组与非粥样斑块组在年龄、BMI、高血压、糖尿病、血脂参数上无统计学差异（P>0.05）, 粥样斑块组患者男性吸烟者居多（P<0.05）。粥样斑块组血清sgp130浓度显著低于非粥样斑块组（314.97±84.39 VS 399.08±79.99 ng/ml, P<0.001）,粥样斑块组血清IL-6浓度显著高于非粥样斑块组（P<0.05）, 粥样斑块组血清sIL-6R浓度和C-反应蛋白浓度(CRP)与非粥样斑块组比较差异无统计学意义。多因素logistic回归分析示血清sgp130浓度是冠状动脉粥样硬化斑块病变存在的预测因子（P=0.018）。血清sgp130浓度与受累冠状动脉数目间呈负相关（r=-0.310,P=0.007）,Gensini评分指数与血清sgp130浓度呈负相关（r=-0.410, P=0.001）,稳定型CAD患者sgp130浓度是Gensini评分指数独立危险因素。结论：稳定型CAD患者血清sgp130浓度与冠状动脉损伤严重程度呈负相关,血清sgp130水平是冠状动脉粥样硬化严重程度血清标志物。     

Interleukin-6 and its soluble receptor in patients with liver cirrhosis and hepatocellular carcinoma

AIM: To evaluate the immunohistochemical localization of interleukin-6 (IL-6) and IL-6 receptor (IL-6R) on tumor tissue specimens from patients with hepatocellular carcinoma (HCC) and the serum levels of IL-6 and sIL-6R in a group of patients with HCC as well as liver cirrhosis (LC) in a group of patients with LC alone and in a control group. METHODS: Three groups of subjects were studied: groupⅠ(n=83) suffering from HCC and LC, groupⅡ(n=72) suffering from LC alone and groupⅢ(n=42) as healthy controls. All patients had hepatitis C virus infection. Serum IL-6 and IL-6R levels were determined using a commercially available ELISA kit. Immunohistochemistry was performed using the streptavidin-biotin complex and rabbit polyclonal antibodies against IL-6 and IL-6R. RESULTS: Immunohistochemistry analysis showed a medium to strong cytoplasmic and membrane reactivity for IL-6 and IL-6R respectively, in at least 40% of cases of HCC, whereas liver cirrhosis patients and controls were negative for IL-6 or showed a very mild and focal dot-like cytoplasmic reaction for IL-6R. Serum IL-6 levels in HCC group were significantly higher than those in LC and control groups (P<0.0001). There was no significant difference in sIL-6R concentrations among 3 groups. When the patients with HCC were divided into groups according to Okuda's classification, a significant serum increase of IL-6 and sIL-6R level was observed from stageⅠto stageⅢ(P<0.02,P<0.0005). When HCC and LC patients were divided into 3 classes of cirrhosis severity according to Child-Pugh, values in HCC patients were significantly higher than those in LC patients for each corresponding class (P<0.01). CONCLUSION: IL-6 serum levels in HCC patients are higher than those in LC patients and controls, suggesting an increased production of this cytokine by neoplastic cells. sIL-6R values are similar in all groups, increasing only in stageⅢHCC patients. These data suggest that they have a closer relationship with the neoplastic mass rather than with the residual functioning hepatic mass.     

T cell immune response is correlated with fibrosis and inflammatory activity in hepatitis B cirrhotics

AIM: To explore the relationship among interferon-γ(IFN-γ) activity, fibrogenesis, T cell immune responses and hepatic inflammatory activity. METHODS: Peripheral blood samples from a total of 43 hepatitis B cirrhotic patients (LC) and 19 healthy controls (NC) were collected to measure their serum levels of IFN-γ, interleukin-2 (IL-2), soluble interleukin-2 receptor (sIL-2R), interleukin-10 (IL-10) and three serological markers of fibrosis including hyaluronic acid (HA), procol-lagen typeⅢpeptide (PⅢP), and typeⅣcollagen were measured using a double antibody sandwich ELISA. Also, serum total bilirubin (TB) and alanine aminotransferase (ALT) were measured by routine measures. RESULTS: The concentrations of serological markers of fibrosis in patients with active cirrhosis (ALC) were significantly higher than those in stationary liver cirrhosis (SLC) or NC groups. The levels of serological markers in HBeAg-positive patients were significantly higher than those in HBeAg-negative patients. In SLC and ALC patients, a negative linear correlation was found between IFN-γlevels and the serological markers of fibrosis. IFN-γand IL-2 levels in the ALC group were significantly higher than those in the SLC and NC groups, but the statistical difference was not significant between the latter two. In contrast, IL-10 levels in the SLC group were significantly higher than that in the NC group, but no significant difference was found between SLC and ALC groups. The sIL-2R level was elevated gradually in all these groups, and the differences were significant. Positive linear correlations were seen between IFN-γactivity and ALT levels (r=0.339, P < 0.05), and IL-2 activity and TB levels (r=0.517, P < 0.05). SIL-2R expression was positively correlated with both ALT and TB levels (r=0.324, 0.455, P < 0.05), whereas there was no statistically significant correlation between IL-10 expression and serum ALT and TB levels (r = -0.102, -0.093, P > 0.05). Finally, there was a positive correlation between IFN-γand IL-2 levels. CONCLUSION: T cell immune responses are correlated with fibrosis and hepatic inflammatory activity and may play an important role in liver cirrhosis.     

Significance of pre-treatment immunological parameters in colorectal cancer patients with unresectable metastases to the liver

BACKGROUND/AIMS: In this study, we have compared the profiles of peripheral blood lymphocyte (PBL) subsets and serum cytokine levels of healthy individuals with those of patients with unresectable liver metastases from colorectal carcinoma before starting regional chemoimmunotherapy. Since the therapeutic responses are limited only to a subset of patients, we hypothesize that the initial status of immunity and individual immune response to a tumor might be significant to the therapeutic outcome. METHODOLOGY: Cellular and humoral immunological parameters were compared between 10 patients with colorectal cancer metastases to the liver responding and non-responding to regional intra-arterial chemo-immunotherapy, and 5 healty individuals. Analyses included a flow cytometric immunophenotyping of peripheral blood mononuclear cells (CD3, CD4, CD8, CD19, CD25, CD28, CD56, CD57, CD80 and HLA.DR), estimation of serum cytokine levels of interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and other immunological parameters are soluble IL-2 receptor (sIL-2), carcinoembryonic antigen (CEA), gastrointestinal cancer-associated antigen (CA 19-9), and C-reactive acute phase protein (CRP). A significantly lower proportion of CD8 lymphocytes and a trend for decreased CD19, CD28 and CD80 was detected among colorectal cancer patients before liver-directed chemotherapy compared to healthy controls. RESULTS: The cancer patients showed a significantly increased population of peripheral NK cells as detected by both CD56+ and CD57+ phenotypes. Elevated serum levels of CRP, IL-4 and TNF-alpha, sIL-2R, but not IL-2, were also demonstrated in cancer patients as compared to controls. Activated CD25+ lymphocytes correlated negatively with CD28+ lymphocytes (r = -0.68, p < 0.01) and less significantly with CD4+ lymphocytes (r = -0.56, p < 0.05). The CD8+ cytotoxic cell subset might be negatively influenced by serum IL-4 (r = -0.57, p < 0.05). Positive correlation was found between sIL-2R and CRP (r = -0.78, p < 0.01), and between sIL-2R and TNF-alpha (r = 0.64, p < 0.05) serum levels in patients with progressive disease during the course of therapy, the initial proportions of CD4+, CD19+ and CD28+ lymphocytes were significantly lower than those among responders. Among humoral parameters, only sIL-2R showed a marginal correlation with therapeutic response, being more elevated among non-responding patients. Pre-treatment serum levels of CEA and CA 19-9 showed correlation with neither therapeutic response nor with any of the cellular or humoral immunological parameters analyzed. CONCLUSIONS: The results may serve as an initial guideline to open a discussion on the rationale of such a panel of tests, hopefully leading to standardized laboratory pre-selection and monitoring of patients treated with regional chemoimmunotherapy.     

Prognostic value of soluble interleukin 2 receptor levels in Langerhans cell histiocytosis

We investigated the prognostic significance of soluble interleukin 2 receptor (sIL-2r) levels in the pre- and post-treatment serum of paediatric patients with Langerhans cell histiocytosis (LCH). Serum levels of sIL-2r from 32 LCH patients and 14 healthy controls were determined using enzyme-linked immunosorbent assay. The LCH patients were classified, evaluated and treated according to the Histiocyte Society's protocols. The following clinical stages were considered: single-system disease (A) divided into single-site (A1; n=4), multiple-site (A2; n=9), and multisystem disease (B) without organ dysfunction (B1; n=5) and with organ dysfunction (B2; n=14). Pretreatment concentrations of sIL-2r were markedly increased at diagnosis in LCH patients compared with controls [in pg/ml, median (range) 9200 (1124-40000) versus 610 (343-800)], P < 0.0001. Levels differed significantly between stages A [3250 (1124-11000)] and B [22750 (3400-40000)], P < 0.05, and between substages A2 and B2, P < 0.05. There was a significant correlation between clinical stages and sIL-2r serum levels, r=0.7996 (P < 0.0001). Patients with > or = 17500 pg/ml of sIL-2r had a 30-month survival of 0.417 (SEM: 0.142) compared with those with levels < 17500 pg/ml, who presented a 30-month survival of 0.848 (SEM: 0.100) (log-rank, P < 0.0001). In multivariate analysis, sIL-2r levels > or = 17500 pg/ml were found to have greater predictive strength than other well-known prognostic factors.     

血清可溶性IL-2受体测定在急慢性肝脏疾病中的意义

目的 探讨急慢性肝病可溶性白介素2受体的改变,为诊断病情演变和预后判定寻找可靠的依据。 方法 健康对照(n=30)研究,采用夹心酶联免疫吸附法测定173例各型肝病患者血清IL-2受体(sIL-2R)水平,包括急性病毒性肝炎80例,慢性乙型肝炎21例,肝炎后肝硬化35例和原发性肝癌37例,并对测定结果进行分析。 结果 各组患者血清sIL-2R均明显高于对照组(P<0.01),其中急性病毒性肝炎黄疸期血清sIL-2R明显高于恢复期(P<0.01),各型急性肝炎之间血清sIL-2R无显著差异(P>0.05);急性肝炎组明显高于慢性肝炎组(P<0.01);慢性乙型肝炎ALT异常组血清sIL-2R明显高于ALT正常组(P<0.01);Child's C级肝炎后肝硬化者明显高于CHild'B,A级者(P<0.01);原发性肝癌者血清sIL-2R水平与肿瘤体积大小有关(P<0.05)。 结论 急慢性肝病患者血清sIL-2R水平均明显增高,其水平的高低在一定程度上反映了机体免疫功能状态和肝细胞损伤的程度。     

Frequently relapsing Crohn's disease is characterized by persistent elevation in interleukin-6 and soluble interleukin-2 receptor serum levels during remission

We examined immune and inflammatory activation during remission in patients with Crohn's disease who presented with various clinical profiles (prolonged remission vs. relapsing disease). Thirty-six patients with at least 3 years' follow-up starting from a remission period were studied retrospectively. Relapses were defined by a retrospective calculation of the Crohn's disease activity index or by the clinical judgement of the physicians in charge of the patients. Disease course over the study period was assessed by the mean number of annual relapses. Analysis used measurements during remission of the following: erythrocytes sedimentation rate, relative lymphocytosis, acid alpha1-glycoprotein, interleukin-6 (IL-6), and soluble interleukin-2 receptor (sIL-2R) serum levels. During the study period 21 patients experienced at least one relapse and 15 did not. Mean serum levels of sIL-2R and mean relative lymphocytosis in remission significantly discriminated between relapsing and nonrelapsing patients. Only the mean sIL-2R serum level was selected by multivariate analysis, with a cutoff value of 82 pM/1 (sensitivity of 76% and specificity of 80%). The only features correlated with mean number of annual relapses in the relapsing patients were mean serum levels of sIL-2R (r=0.58, P=0.015) and IL-6 in remission (r=0.45, P=0.039). Multivariate analysis demonstrated statistical significance only for the mean serum level of IL-6 (P=0.014). In Crohn's disease the persistent elevation in sIL-2R serum levels during remission corresponds to chronic active disease, while high serum levels of IL-6 in these patients is associated with a high frequency of relapse.     

Evidence for the regulation of levels of plasma adhesion molecules by proinflammatory cytokines and their soluble receptors in type 1 diabetes

OBJECTIVES: To investigate the regulation of soluble adhesion molecules by tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and relationships with circulating cytokine receptors, in vivo, in type 1 diabetes. DESIGN: Cross-sectional study. SETTING: University hospital diabetes clinic. SUBJECTS: A total of 47 non-nephropathic, Caucasian type 1 diabetics and 39 nondiabetic controls. OUTCOME MEASURES: Plasma levels of TNF-alpha, IL-6, their soluble receptors and adhesion molecules intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), sE-selectin and von Willebrand factor (vWF), and risk factors for cardiovascular disease. RESULTS: Plasma concentrations of IL-6 were elevated in diabetic patients compared with controls [median (interquartiles) 1.28 (0.89-2.65) vs. 0.66 (0.45-1.73) pg mL(-1): P=0.016], and in these patients IL-6 and soluble IL-6 receptor (sIL-6R) levels correlated with concentrations of sICAM-1 (r = 0.41, P = 0.012 and r = 0.31, P = 0.04, respectively). Tumour necrosis factor-alpha soluble receptor-2 (sTN-FRII), but not TNF-alpha or tumour necrosis factor soluble receptor-1 (sTNFRI), was elevated in diabetic subjects (P = 0.027). Plasma TNF-alpha levels correlated with sVCAM-1 (r = 0.39, P = 0.008), triglycerides (r = 0.36, P = 0.02 1) and diastolic blood pressure (r = 0.35; P = 0.024). Both sTNFRI and sTNFRII correlated with blood pressure (r = 0.46, P = 0.002; r = 0.32, P = 0.034) and triglycerides (r = 0.33, P = 0.033; r = 0.29, P = 0.05). In contrast, HDL-cholesterol and triglyceride were related to sE-selectin (r = -0.45 and +0.45; both P < 0.001). Neither sE-selectin nor vWF were related to cytokine concentrations. Finally, both TNF-alpha and sIL-6R correlated sTNFRI and RII (r = 0.44-0.49, P < 0.001). None of these interactions were apparent in control subjects. CONCLUSIONS: (i) IL-6, through effects on sICAM-1, and TNF-alpha via effects on sVCAM-1, may promote vascular adhesion; (ii) plasma levels of TNF-alpha are associated with dyslipidaemia and increased blood pressure, adding to vascular disease risk; (iii) the actions of both cytokines are probably modified by altered production of soluble receptors in diabetic subjects.     

Lack of association between hyperprolactinemia and soluble IL-2 receptor levels in systemic lupus erythematosus

The aim of the study was to evaluate the association between hyperprolactinemia and T lymphocyte activation through the soluble IL-2 receptor (sIL-2R) in systemic lupus erythematosus (SLE) patients. Seventy SLE patients, 18 of them with hyperprolactinemia (HPRL), were compared with 18 normoprolactinemic (NPRL) patients and 10 age-matched healthy blood-bank donor women. Patients were evaluated by means of the SLE activity index (SLEDAI). Total serum IgG and sIL-2R levels were determined by an ELISA assay. Differences between sIL-2R and IgG serum levels in patients and controls were examined by Kruskal-Wallis analysis and a Spearman r correlation to determine the association between sIL-2R, IgG and prolactin (PRL) levels. IgG and sIL-2R serum levels did not differ significantly between HPRL and NPRL patients: 1827.3 (1428-2226) vs 2028.8 (1586-2467) mg/dl and 882.2 (511-1254) vs 740.1 (534-946.4) U/ml, respectively (confidence interval 95%). In the total SLE group, sIL-2R and IgG serum levels were positively associated (P = 0.0009), however, this was not the case for sIL-2R and PRL (P > 0.49). We did not demonstrate an association between HPRL and lymphocyte activation measured through serum sIL-2R in female patients with SLE.     

IL-6联合sIL-6R对人甲状腺细胞增殖及相关基因表达的影响

目的 探讨白细胞介素-6(IL-6)联合可溶性IL-6受体(sIL-6R)对人甲状腺细胞增殖及相关基因表达的影响.方法 通过手术标本获得甲状腺组织,采用甲状腺细胞培养技术,提取并培养甲状腺细胞.以不同浓度(0、1、5、10、20 μg/L)的IL-6分别联合sIL-6R 100μg/L干预细胞24、48 h,予以IL-6单克隆抗体进行阻断.以MTT法检测IL-6干预后的细胞活力,并在显微镜下观察细胞形态学变化;以RT-PCR测定IL-6、IL-6受体及糖蛋白130的表达,实时定量PCR检测IL-6干预后甲状腺细胞的钠-碘转运体(NIS)、甲状腺过氧化物酶(TPO)、甲状腺球蛋白(TG)、促甲状腺激素受体(TSHR)基因的表达.结果 甲状腺细胞表达IL-6、糖蛋白130,但几乎不表达IL-6受体.IL-6联合sIL-6R培养24、48 h后,甲状腺细胞活力显著增加(F=65.28、78.47;P均＜0.05),而使用IL-6单克隆抗体进行阻断,发现随着IL-6单克隆抗体浓度的增加,甲状腺细胞活性亦显著下降(F=60.15,P＜0.05);随着IL-6浓度的增加,甲状腺细胞数量越多,体积越大.IL-6能够抑制NIS、TPO、TG基因的表达(t=6.92～12.12,P均＜0.05),而对TSHR基因无明显影响.结论 IL-6联合sIL-6R能够促进甲状腺细胞增殖,同时也能够抑制甲状腺相关基因的表达.     

Profile of soluble cytokine receptors in Crohn's disease

INTRODUCTION: Soluble cytokine receptors (sCRs) modulate the in vivo activity of cytokines. Deficient sCR production could participate in the pathogenesis and course of Crohn's disease (CD). The aim of the study was to examine the profile of sCRs in CD patients and their modulation by infliximab and corticosteroids. METHODS: We prospectively examined active CD patients (aCD) treated with either infliximab (n = 21) or corticosteroids (n = 9), CD patients in clinical remission (rCD, n = 20), ulcerative colitis patients (UC, n = 24), and healthy subjects (HS, n = 15). Cultures of colonic biopsies were also examined from CD inflamed (n = 8), CD non-inflamed (n = 7), and healthy mucosa (n = 8). Levels of tumour necrosis factor alpha (TNF-alpha), soluble TNF receptor I (sTNFRI), soluble TNF receptor II (sTNFRII), interleukin 1beta (IL-1beta), soluble IL-1 receptor I (sIL-1RI), soluble IL-1 receptor II (sIL-1RII), IL-6, soluble IL-6 receptor (sIL-6R), and sgp130 were measured using ELISA. RESULTS: Higher levels of sTNFRI (p<0.05, p<0.01), sTNFRII (p<0.01, p<0.01), sIL-1RI (p<0.05, NS), IL-6 (p<0.01, p<0.01), and sIL-6R (p<0.05, NS) were observed in aCD compared with rCD and HS. Interestingly, sIL-1RII (p<0.05, p<0.01) and sgp130 (p<0.01, p<0.01) were profoundly decreased in aCD compared with rCD and HS, and were negatively correlated with CRP. Deficient production of sIL-1RII was specific to CD (not observed in ulcerative colitis), and was further confirmed at the mucosal level. Infliximab decreased sTNFRII at one and four weeks (p<0.05) and enhanced sIL-6R levels at one week (p<0.05). Corticosteroids increased sIL-1RII levels at one week (p<0.05). CONCLUSION: CD is associated with dysregulated production of sCRs. Deficiency in sIL-1RII and sgp130 may be essential to CD pathogenesis. Their replacement through the use of fusion proteins could represent future alternative therapeutic strategies for CD.     

Treatment with fluvastatin rapidly modulates, via different pathways, and in dependence on the baseline level, inflammation in hemodialysis patients

BACKGROUND: Hemodialysis (HD) patients are frequently in an elevated inflammatory state which is correlated to the atherosclerosis-related and overall morbidity and mortality in this population. Statins, beyond their antilipidemic effects, are also considered to have anti-inflammatory, immunomodulating and antioxidant properties. The individual response of HD patients to a short course of fluvastatin, the mechanisms involved in the immunomodulating and anti-inflammatory effects of this drug and the time interval to the appearance of these effects are investigated in this longitudinal study. METHODS: In a group of 51 HD patients, fluvastatin 40 mg/day was administered for 4 weeks. Serial measurements of the lipid profile, C-reactive protein (CRP), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), interleukin-10 (IL-10), and serum oxidized LDL (ox-LDL), were performed before, during, and after the treatment period. RESULTS: Total cholesterol was significantly reduced after 14 days of treatment with fluvastatin (from mean +/- SD 216.7 +/- 34.3 to 179.2 +/- 42.3 mg/dl, p < 0.001). IL-6 and ox-LDL were reduced on day 28 (p < 0.001 and p < 0.01, respectively) and IL-10 was increased on day 14 (p = 0.05); CRP did not change significantly during the treatment period while sIL-6R was increased on day 28 of fluvastatin administration (p < 0.05). In a subgroup of patients with CRP, IL-6, sIL-6R, and ox-LDL baseline serum values > or = the median and IL-10 < or = the median, CRP was reduced on day 28 of fluvastatin treatment (p < 0.01), IL-6 and ox-LDL were reduced earlier, on day 14 (p = 0.05 and p < 0.05, respectively) while sIL-6R did not change significantly during the treatment period. CONCLUSIONS: Treatment with fluvastatin rapidly modulates inflammation in HD patients. Enhancement of anti-inflammatory mechanisms and attenuation of the inflammatory and oxidative state contribute to this modulation. Patients in an elevated baseline inflammatory state respond more rapidly and effectively to the treatment. This immediate and multi-potent action of the statins could be clinically useful in acute atherosclerosis complications or in the treatment of chronic inflammation in HD patients.     

The influence of corticosteroids on IL-6/IL-6R system in patients with Graves' ophthalmopathy

IL-6 and its soluble receptor (IL-6R) appeared as reliable markers of inflammation activity in autoimmune diseases. The aim of the study was an estimation of serum IL-6 and sIL-R in patients with Graves' disease with ophthalmopathy during treatment with corticosteroids to assess their potential as a guideline of immunosuppressive therapy. We detected serum HIL-6 and IL-6R in three groups of subjects: 18 patients with clinical symptoms of ophthalmopathy (Clinical Activity Score > or = 3, anamnesis of GO > or = 1 yr), 16 patients with Graves' disease without ophthalmopathy (Gd) and 14 healthy volunteers. Corticosteroid therapy consisted of intravenous infusions of methylprednisolone (MP) and subsequent treatment with oral prednisone (P). The serum samples were collected 24 hours before MP, 24 hours after MP, 14 days of treatment with prednisone and after the end of the corticosteroid therapy. The levels of soluble IL-6 and IL-6R in the serum were determined by the ELISA method (Quantikine kit, R&D Systems, Minneapolis). The statistical significance was estimated by the Mann-Whitney U-test. IL-6 concentration was significantly increased in patients with GO in comparison to the controls (12.4 +/- 3.7 vs 11.8 +/- 3.2; p < 0.05). After MP treatment in corticosteroid-responsive patients (improvement in CAS < or = 1) serum concentration of sIL-6R decreased significantly in comparison to pretreatment values (32.8 +/- 4.2 vs 28.6 +/- 4.9; p < 0.05). We found a positive correlation between IL-6 concentration and degree of proptosis. CONCLUSIONS: 1. IL-6/IL-6R system plays an important role in the pathogenesis of GO. 2. IL-6R is a potent prognostic factor for efficacy of the immunotherapy but further investigations are needed.     

In vitro production of TNF-alpha,IL-6 and sIL-2R in Chinese patients with ulcerative colitis

AIM:To determine the tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and soluble interleukin 2 receptor (sIL-2r) from peripheral blood mononuclear cells (PBMC) in 25 Chinese patients with ulcerative colitis and 20 healthy controls.METHODS:PBMC were isolated by density gradient centrifugation of heparinized blood and cultures for 24 or 48 hours by stimulation with LPS or PHA. TNF-alphaand sIL-2r were measured by ELISA method and IL-6 measured by biossay.RESULTS:TNF-alphaproduction stimulated by LPS and sIL-2r production by PHA in ulcerative colitis were significantly lower than in healthy controls (TNF-alpha509(46-7244)ng/L vs 1995(117-18 950)ng/L, P < 0.05; sIL-2r 320U/mlplus minus 165U/ml vs 451U/mlplus minus 247U/ml, P < 0.05).Spontaneous TNF-alphaand sIL-2r production were not significantly different between ulcerative colitis and controls (TNF-alpha304(46-7044)ng/L vs 215(46-4009)ng/L,P > 0.05; sIL-2r 264U/mlplus minus 115U/ml vs 236U/mlplus minus139U/ml, P>0.05). IL-6 production by spontaneous release from PBMC in ulcerative colitis group was 109U/mlplus minus 94U/ml vs 44U/mlplus minus 39U/ml for those in healthy controls, P < 0.01. IL-6 stimulated by LPS in ulcerative colitis group was (261U/ml plus minus 80U/ml) higher than in healthy controls (102U/mlplus minus 54U/ml, P < 0.01). No correlation of TNF-alpha, IL-6, sIL-2r production was found to disease activity, disease location and medication.CONCLUSION:Cytokine production from PBMC was also disturbed in Chinese patients with ulcerative colitis.     

Interleukin-6, soluble interleukin-2 receptor and soluble interleukin-6 receptor in the sera of patients with different histological patterns of rheumatoid synovitis

OBJECTIVE: The present study was conducted to investigate whether the serum levels of interleukin 6 (IL-6), soluble IL-2 receptor (sIL-2R) and sIL-6R are associated with the morphological appearance of rheumatoid arthritis (RA). METHODS: Using the ELISA technique we measured the IL-6, sIL-2R and sIL-6R concentrations in the serum of 34 patients with RA and 28 patients with osteoarthritis (OA). Histological analysis of synovial samples distinguished 2 types of rheumatoid synovitis. Twenty-one RA specimens presented diffuse infiltrates of mononuclear cells without any specific microanatomical organization. In remaining 13 samples the formation of lymphocytic follicles with germinal center-like structures was found. RESULTS: Serum levels of IL-6, sIL-2R and sIL-6R were elevated in patients with RA compared to the OA control group (p < 0.001, p < 0.001 and p < 0.05 respectively). Concentrations of IL-6 and sIL-2R were highest in the serum of RA patients with follicular synovitis in comparison to patients with diffuse synovitis (p < 0.001 and p < 0.01 respectively) and could distinguish RA patients with these two histological variants of the disease. Serum levels of IL-6 and sIL-2R correlated with markers of disease activity such as ESR and CRP levels. In addition, the clinical data suggest a more severe disease among RA patients with follicular synovitis. CONCLUSION: Distinct histological types of rheumatoid synovitis associated with unique serum concentrations of IL-6 and sIL-2R reflect levels of disease activity and confirm the concept of RA heterogeneity.