Effect of interleukin 6 on basal and FSH-stimulated secretion of estradiol and progesterone by human granulosa cells in vitro

Aim: To determine the effects of interleukin-6 (IL-6) on the secretion ofestradiol and progesterone by human granulosa cells in vitro. Methods:Granulosa cells were obtained from infertile patients undergoing IVF ETtreatment and cultured with serum-free supplemented HAM's F10 medium.In the absence or presence of FSH, granulosa cells were treated with differ-ent concentrations of gene recombinant human iterlukin-6 (rhIL-6). Themedia were collected after 24, 48, 72 and 96 h and assayed for estradiol andprogesterone. IL-6 and R mRNA was determined by means of RNA slotblot. Results: IL-6 had a significant inhibitory effect on estradiol secre-tion, especially in the presence of FSH. IL-6 inhibited the FSH-stimulatedprogesterone secretion, but not the basal progesterone release. The inhibi-tion shows certain degrees of dose- and time-dependency. Conclusion:IL-6 participates in the regulation of ovarian function through its inhibitoryeffect on FSH-stimulated steroidogenesis by granulosa cells.     

Interleukin-6 is an independent predictor of mortality in patients starting dialysis treatment.

BACKGROUND: The mortality rate is high among end-stage renal disease (ESRD) patients, and recent evidence suggests that this may be linked to inflammation. The activity of interleukin-6 (IL-6) and its soluble receptor (sIL-6R) are markedly up-regulated in ESRD patients, and plasma IL-6 levels predict outcome in haemodialysis (HD) patients. However, it has not been established whether elevated plasma IL-6 also predicts outcome in ESRD patients treated by peritoneal dialysis (PD), and how it relates to the data on HD patients. The predictive power of sIL-6R levels on outcome is also unknown in this patient population. METHODS: To determine whether or not plasma IL-6 and sIL-6R predict patient survival, we studied 173 ESRD patients (62% males, 53+/-1 years of age) near the initiation of dialysis treatment (99 PD, 74 HD patients). The patients were followed for a mean period of 3.1+/-0.1 years (range 0.1-7.1 years) and were stratified at the start of dialysis treatment according to age, gender, presence of cardiovascular disease, malnutrition (determined by subjective global assessment), diabetes mellitus, and IL-6 and sIL-6R plasma levels. RESULTS: A significantly different (P<0.0001) mortality rate was observed in different groups when patients were divided into quartiles according to IL-6 levels. Furthermore, the same differences were observed, less notably however, for sIL-6R (P<0.05). When patients were stratified according to IL-6 quartiles and analysed separately according to the different initial treatment groups, a similar profile of survival was observed for PD (P<0.01) and HD (P<0.05) patients. In a Cox proportional hazard model adjusting for the impact of age, malnutrition, diabetes mellitus and male gender, log IL-6 values were independently associated with poor outcome (P<0.05). CONCLUSIONS: The present study demonstrates that the strong predictive value of elevated IL-6 levels for poor outcome in ESRD patients is similar in both HD and PD patients starting treatment.     

急性胰腺炎合并肝损伤时IL-6、氧自由基变化及IL-2、川芎嗪干预的实验研究

目的：探讨IL－6、氧自由基在急性胰腺炎（acute pancreatitis，AP）合并肝损伤中的作用，及重组人白介素－2（IL－2）、川芎嗪的治疗价值。方法：SD大鼠112只，随机分为14只，每组8只，5％牛磺胆酸钠逆行胰胆管内注射诱发大鼠AP动物模型，检测血浆IL－6、SOD、MDA、ALT、AST、LDH、LIP、AMY，并观察肝、胰病理变化。结果；①AP组血浆AMY、LIP、ALT、AST、LDH明显升高（P＜0．05或0．01），镜下可见胰腺水肿、炎细胞浸润、坏死1肝脏肝窦充血、细胞浊肝及坏死，且损伤程度随时限延长而加重；②AP各组血浆IL－6明显升同（P＜0．01）；③AP各组MDA明显高（P＜0．01）、SOD明显降低（P＜0．01）。④IL－2治疗组、川芎嗪治疗组有IL－2、川芎嗪联合且与NS组比较血浆IL－6、MDA水平明显下降（P＜0．05），SOD明显升高（P＜0．05），胰、肝病理损害程度减轻，并且AMY、LIP、ALT、AST、LDH均明显降低（P＜0．05），平均存活时间明显延长（P＜0．05）；联合应用组降低IL－6、MDSA水平和减轻胰腺坏死优于单药组。结论：①IL－6、氧自由基在急性胰腺炎合并肝损伤程度和明显升同，起损伤作用，而SOD明显降低，其保护作用减弱。检测血浆IL－6、MDA、SOD可作为判断AP合并肝脏损伤程度和预后的指标；②大鼠急性胰腺合并肝损伤过程中应用IL－2、川芎嗪显示出良好的效果，联合应用于亿于这两药的单独应用。     

Interleukin-6 and Development of Vasospasm after Subarachnoid Haemorrhage

Summary  The authors characterized the role of interleukins in the cerebrospinal fluid (CSF) in the development of vasospasm after subarachnoid haemorrhage (SAH), particularly interleukin-6 (IL-6).  Concentrations of interleukin-1β (IL-1 β), IL-6, and interleukin-8 (IL-8) were measured serially in CSF of 24 patients and in serum of 9 patients with SAH and correlated clinically. Additionally, the effects of the same cytokines on the cerebral arteries of dogs were analyzed on angiograms after intracisternal injection. Changes in levels of eicosanoids, angiogenic factors, and soluble cell adhesion molecules were investigated in the CSF of injected dogs.  CSF concentrations of IL-6 and IL-8 were elevated significantly above control levels from the acute stage of SAH until the chronic stage. Patients with symptomatic vasospasm had significantly higher levels of IL-6 as well as IL-8 in CSF on days 5 and 7. Intracisternal injection of IL-6 induced long-lasting vasoconstriction in five out of eight dogs, while IL-8 did not. The diameter of canine basilar artery after IL-6 was reduced 29±5% from pretreatment diameter at 8 hours. Prostaglandins E₂ and I₂ were elevated in CSF for the first 4.5 hour of this IL-6-induced vasospasm. Neither angioenic factors such as platelet-derived growth factor-AB and vascular endothelial growth factor nor soluble cell adhesion molecules were significantly elevated in CSF.  IL-6, which increases to very high concentrations in CSF after SAH, may be important in inducing vasospasm, as IL-6 produced long-lasting vasoconstriction in the canine cerebral artery, which may be partly related to activation of the prostaglandin cascade.     

IL-6对人精子顶体反应影响机制的初步探讨

目的:探讨IL-6对人精子顶体反应(AR)的影响机制。方法:采用BAEE/ADH法测定精子顶体酶的活性,以及通过FITC-PSA法检测精子顶体反应。结果:IL-6可诱导精子顶体酶及超氧化物歧化酶(SOD)的活性,促进精子顶体反应;胞外Ca2+单独不能诱导精子顶体反应,且没有胞外Ca2+的参与,IL-6也不能诱导精子顶体反应;蛋白激酶C(PKC)抑制剂calphC能逆转IL-6诱导的精子顶体反应。结论:IL-6对精子顶体反应有一定的促进作用,可能通过诱导精子的顶体酶和SOD活性等途径来实现,在此作用中,也涉及了PKC的激活,且还需要外源性Ca2+的参与。     

Interaction of interleukin-6 and estrogen receptor gene polymorphisms on bone mass accrual in Chinese adolescent girls

We assessed the main and interaction effects of interleukin-6 and estrogen receptor gene polymorphisms on bone mass accrual in Chinese adolescent girls. A total of 228 premenarche Chinese girls (9-11.5 years old) were recruited for a 2-year follow-up study. Bone mineral density (BMD) at the total body, lumbar spine (L1-L4), and total left hip were measured by dual-energy X-ray absorptiometry at baseline and follow-up. The -174G/C and -634C/G polymorphism of IL-6 gene, and PvuII and XbaI polymorphisms of the estrogen receptor (ER)-alpha gene, were determined. The -634C/G polymorphism of the IL-6 gene and PvuII polymorphism of ER-alpha gene were significantly associated with bone mass accrual after adjusting the potential confounding factors. Girls with pp genotype of ER-alpha gene had greater percentage accrual in BMD of total body (P = 0.010) and femoral intertrochanter (P = 0.038) than their PP and Pp counterparts. Girls with CC genotype of IL-6 -634G/C gene had higher percentage accrual in BMD of total body (P = 0.032) and femoral trochanter (P = 0.048) than their CG + GG counterparts. Significant interaction effects of IL-6 -634C/G polymorphism and ER-alpha PvuII polymorphism were observed on percentage change in BMD of total left hip (P = 0.009) and femoral intertrochanter (P = 0.007). The genotype CC (IL-6 -634C/G) x pp (ER-alpha PvuII) was associated with greater BMD accrual than other genotype combination in Chinese adolescent girls. We found that the IL-6 -634C/G and ER-alpha PvuII polymorphism were significantly associated with BMD accrual and that they have an interactional effect on BMD accrual in Chinese adolescent girls.     

Interleukin-6 is a stronger predictor of total and cardiovascular mortality than C-reactive protein in haemodialysis patients.

BACKGROUND: Despite the well known association between interleukin-6 (IL-6) and cardiovascular mortality, no study has so far verified whether IL-6 adds prognostic information to that provided by C-reactive protein (CRP). METHODS: A cohort of 218 haemodialysis patients from four different dialytic centres was followed-up retrospectively. Plasma IL-6 and CRP concentrations were determined. Full information on co-morbidities was available in 162 patients. RESULTS: With respect to the lowest quartile (< 3.6 pg/ml for IL-6, and < 2.2 mg/l for CRP), the crude relative risk (RR) of death from all causes of the upper quartile (> 13.9 pg/ml for IL-6, and > 12.8 mg/l for CRP) was 5.20 (95% confidence interval 2.06-13.011) for IL-6 and 3.16 (1.41-7.12) for CRP. When both variables were included, the estimates were 4.10 (1.30-12.96) for IL-6 and 1.29 (0.47-3.57) for CRP. As to continuous variables, the relationship between both variables and mortality tended to level off for the highest values, but became fairly linear after log transformation of the variables. For one unit SD of the log (variable), the RR was 2.09 (1.52-2.88) for IL-6 and 1.66 (1.23-2.24) for CRP. When they were included in the same model, the estimates were 1.90 (1.18-2.82) for IL-6 and 1.16 (0.81-1.66) for CRP. CONCLUSIONS: IL-6 has a stronger predictive value than CRP for cardiovascular mortality and provides independent prognostic information, while conveying most of that provided by CRP.     

Interleukin-6 production induced in peripheral blood mononuclear cells by a serum factor from IgA nephropathy patients is inhibited in vitro by specific sugars

The basal production of IL-6 by cultured peripheral blood mononuclearcells (PBMC) from patients with IgAN, is markedly higher (A,109 pg/ml) as compared to that of PBMC of either patients withoutclinical signs (I, 39 pg/ml) or appropriate controls (C, 44pg/ml). When PBMC from healthy subjects were incubated in thepresence of sera from patients A, the IL-6 production was stronglyenhanced. No such an effect was observed by stimulating PBMCwith sera from the other two groups of subjects (I, C). In anotherexperiment we observed that the IL-6 production stimulated byserum from patients A could be inhibited by addition of specificmonosaccharides. The inhibitory effect was rapidly abolishedwhen the sugar-containing medium was substituted with the originalone. Finally molecular components from serum of A were grosslyseparated by gel column chromatography. Individual fractionswere incubated with PBMC of C: fractions with Mr > 30 000highly stimulated the release of IL-6 (up to 1320 pg/ml); fractionswith lower molecular weight were inactive. The data suggest the presence of an IL-6 releasing factor inthe serum of IgAN patients. Although the chemical nature ofsuch a factor is not yet established, the observations reportedfocus our attention to the lectins family. Since this factorseems potentially important in the understanding of the pathogenesisof IgAN, both its isolation and structural/functional characterizationdeserve further efforts.     

LY354740减轻氯胺酮麻醉后幼鼠认知功能障碍及对海马炎性反应的影响

目的探讨LY354740预先给药减轻氯胺酮麻醉致幼鼠认知功能障碍及海马炎性反应的影响。方法清洁级雄性C57BL/6小鼠48只,21日龄,重约22~32 g,按照随机数字表法分为3组(每组16只);生理盐水组(NS组)、氯胺酮组(Ket组)、LY354740预给药组(LY组)。LY组于每天第1次注射氯胺酮前30 min腹腔注射LY354740 15 mg/kg余同Ket组;Ket组和LY组每天腹腔注射氯胺酮30 mg/kg共3次、间隔30 min,连续5天;NS组每次注射等量生理盐水。生理盐水组(NS组)、氯胺酮组30 mg/kg(Ket组)、LY354740预处理组(LY组)。LY组于每天首次腹腔注射氯胺酮前30 min注入LY354740 15 mg/kg,余同另两组。Ket组和LY组于每天同一时间点腹腔注射氯胺酮30 mg/kg、间隔30 min注射一次,共3次,连续5 d。所有小鼠均在末次给药结束后24 h进行认知功能测试(水迷宫和旷场实验),测试完毕后立即处死大鼠,取海马组织,以酶联免疫吸附(ELISA)法,测定海马IL-1、IL-6、TNF-α的含量。结果与NS组比较,Ket组逃避潜伏期时间明显延长,平台象限停留时间和旷场中心区停留时间缩短,平台穿越次数减少;海马IL-1、IL-6、TNF-α含量升高(P0.05),LY组上述指标差异无统计学意义(P0.05)。与Ket组比较,LY组逃避潜伏期明显缩短,原平台停留时间和旷场中心区停留时间延长,穿越原平台次数增多;海马IL-1、IL-6、TNF-α含量降低(P0.05)。结论 LY354740预先给药可改善氯胺酮麻醉所致幼鼠认知功能障碍,其机制可能与抑制海马炎性反应有关。     

结直肠癌患者手术前后血清中IL-6和NO水平的临床意义

目的探讨结直肠癌患者手术治疗前后血清中IL-6和NO水平变化及其临床意义。方法对40例结直肠癌患者分别采用酶联免疫分析法和化学比色法测定手术前后血清中的IL-6和NO水平,并与10名正常健康人作比较。结果结直肠癌患者手术前血清中IL-6水平高于正常人（P〈0.05）,NO水平明显低于正常人（P〈0.01）;经手术治疗2周后,患者血清IL-6水平较治疗前降低（P〈0.05）,而NO水平明显升高（P〈0.05）。结论结直肠癌患者血清中IL-6和NO水平的变化,对病情和预后判断具有重要的临床意义。     

The cytokine response in a patient undergoing surgery for an ACTH-producing tumor

The administration of glucocorticoids has been used to inhibit the cytokine production in patients undergoing cardiac surgery during cardiopulmonary bypass. In this case report the cytokine response in a 43-year-old man undergoing operation for an ACTH-producing lung tumor is presented. There had been clinical symptoms for about 18 months and 8 months before operation elevated serum concentrations of ACTH and cortisol were measured. The patient underwent thoracotomy with removal of the tumor and the cytokine response in relation to surgery was measured as plasma concentrations of IL-lα, IL-6, TNFα and TNFβ. With the long-lasting high endogenous glucocorticoid production low or undetectable cytokine levels were expected in this patient. However, a marked and prolonged IL-6 and TNFβ response was measured while IL-1α and TNFα were detectable in only a few samples. The cytokine response in this patient was different from the response normally found in patients undergoing major surgery.     

熊去氧胆酸通过干扰白介素-10对小鼠肥胖风险的影响

目的:探索熊去氧胆酸(UDCA)通过干扰脂肪组织中白介素-10(IL-10)的水平,对高脂饲料诱导小鼠肥胖风险的影响。方法:将C57BL/6J雄鼠简单随机化分为:Control组、DIO组、+UDCA组及+UDCA+IL-10组,于诱导0、6及8周后测量体重。取小鼠肠系膜白色脂肪(mesenteric white adipose tissue,mWAT),ELISA和western-blot法检测mWAT中IL-10和IL-10Rα的蛋白浓度;RT-PCR法检测产热基因的表达水平。结果:诱导6周后,Control组小鼠体质量较其它高脂诱导组低,差异有统计学意义(P<0.05);8周后,高脂诱导小鼠中,DIO组小鼠体重最高,+DUCA+IL-10组次之,+DUCA组最低。DIO组mWAT中IL-10含量较Control组高(37.13pg/mg vs 16.29pg/mg,P<0.01),+DUCA组的IL-10含量(19.04pg/mg)较DIO组低(P<0.01),+DUCA+IL-10组的IL-10含量(33.87pg/mg)较+DUCA组高(P<0.05)。此外,各组mWAT中IL-10Rα水平的变化趋势与IL-10相似。+DUCA组mWAT中多个线粒体产热基因的表达较DIO组上调(P<0.05)。结论:UDCA可减少高脂诱导小鼠白色脂肪中IL-10和IL-10Rα水平,增加脂肪细胞线粒体产热基因的表达,降低小鼠的肥胖风险;该效果可被外源性IL-10削弱。     

Interleukin-6 promoter polymorphism is associated with bone quality assessed by calcaneus ultrasound and previous fractures in a cohort of 75-year-old women

Interleukin 6 (IL-6) is a multifunctional cytokine and a potent stimulator of bone resorption and has been implicated in the pathogenesis of osteoporosis in postmenopausal women. The aim of this study was to investigate if a functional IL-6 promoter polymorphism (–174) was related to bone mass and fractures in a cohort consisting of 964 postmenopausal Caucasian women aged 75 years. Bone mineral density (BMD; g/cm²) of the femoral neck, lumbar spine and total body was measured using dual energy X-ray absorptiometry (DXA). Quantitative ultrasound (QUS) was also measured in the calcaneus and quantified as speed of sound (SOS; m/s), broadband ultrasound attenuation (BUA; dB/MHz), and stiffness index (SI). IL-6 genotypes was determined by restriction fragment length polymorphism (RFLP) using the restriction enzyme NlaIII. The frequencies of the different IL-6 genotypes were 27.5% (GG), 47.9% (GC), 24.6% (CC). The IL-6 polymorphism (presence of G) was independently related to a lower stiffness (=–0.07; P=0.03) and BUA (=–0.08; P=0.02), but not to BMD at any site measured by DXA. In the cohort, 420 subjects (44%) reported at least one fracture during their lifetime, and 349 (36%) reported at least one fracture after the age of 50. Using binary logistic regression, the IL-6 polymorphism (presence of G) was significantly related to an increased risk of a previous fracture during life (odds ratio 1.46, 95% CI 1.08–1.97) and to an increased risk of a fracture occurring after 50 years of age (odds ratio 1.37, 95% CI 1.004–1.88). The risk was further increased for fractures grouped as osteoporotic fractures (odds ratio 1.67, 95% CI 1.14–2.45), including forearm fractures (odds ratio 1.59, 95% CI 1.05–2.40). In conclusion, presence of G allele in the IL-6 promoter polymorphism at position –174 is independently related to previous fractures in postmenopausal women. This association may be related primarily to an altered bone quality identified by QUS and not a lower bone mass. This is also the first demonstration of association of IL-6 gene polymorphism to calcaneal QUS.     

免疫性不育男性精浆白细胞介素6和可溶性细胞黏附分子1分析

目的:检测男性免疫性不育患者精浆白介素6(IL-6)和可溶性细胞粘附分子1(s ICAM-1)水平,探讨炎症细胞因子与男性免疫性不育的关系。方法:按精子膜表面抗体免疫珠试验结果将临床疑为不育症患者分为免疫性不育组(Ig A或Ig G抗体黏附的精子数≥50%)41例、其他原因不育A组(10%≤Ig A或Ig G抗体黏附的精子数50%)37例,其他原因不育B组(Ig A或Ig G抗体黏附的精子数10%)45例。按白细胞过氧化物酶染色结果将免疫性不育患者分为免疫性白细胞阳性组和免疫性白细胞阴性组;选择同期因女方因素不孕前来检查的生育力评估正常的健康男性31例作为对照组。统计分析各组炎症因子精浆表达水平及精浆主要参数的差异。精液液化时间通过肉眼观察和显微镜进行识别判读,精子浓度及活力用计算机辅助精子分析系统,精子存活率采用低渗膨胀实验(HOS),抗精子抗体采用免疫珠试验(IBT);白细胞过氧化物酶染色采用正甲苯胺法,IL-6和s ICAM-1的含量测定采用酶联免疫吸附(ELISA)法。结果:各不育组与对照组比较,精子存活率和前向运动精子百分率有统计学差异(P0.05或P0.01)。免疫性不育组、其他原因不育A组、其他原因不育B组和对照组精浆IL-6(ng/L)、s ICAM-1(ng/ml)水平分别为37.92±17.01、89.15±41.82,22.23±13.77、67.81±33.24,18.75±14.32、53.25±27.09,9.47±5.76、19.46±9.77。各不育组与对照组比较,IL-6、s ICAM-1均有非常显著性差异(P0.01),免疫性不育组与其他原因不育两组分别比较差异均有统计学意义(P0.05或P0.01)。免疫性白细胞阳性组和免疫性白细胞阴性组精浆IL-6(ng/L)、s ICAM-1(ng/ml)的水平分别为49.25±21.46、104.36±46.41和31.38±15.54、80.38±35.52,两者比较均有统计学差异(P0.05)。结论:男性精浆中IL-6和s ICAM-1升高可能与免疫性不育有关。     

慢性阻塞性肺疾病患者血清IL-6与FEV1相关性研究

目的探讨稳定期COPD患者血清IL-6与FEV1的关系。方法选择稳定期COPD患者60例,测定肺功能,ELISA法检测COPD患者和健康志愿者血清IL-6,分析COPD患者血清IL-6与FEV1之间的相关性。结果logIL-6与FEV1呈负相关（r值为-0．602,P〈0．01）。结论血清IL-6在稳定期COPD患者中增高,可在一定程度上反映COPD患者的全身炎症程度,并且与FEV1呈负相关,可作为预测稳定期COPD患者病情及预后的有效指标。