An interleukin-10 promoter polymorphism may influence tumor development in renal cell carcinoma

PURPOSE: Polymorphisms in the promoter of the interleukin-10 (IL-10) gene may influence tumor development by altering the levels of IL-10 present in the serum or tumor microenvironment. In this study we looked for evidence of specific polymorphisms of the IL-10 promoter and whether lymphocyte expression of IL-10 correlates with specific genotypes. MATERIALS AND METHODS: Archival, paraffin embedded renal cell carcinoma tissue from 166 patients and 161 controls were genotyped for the IL-10-1082 single nucleotide polymorphism using real-time polymerase chain reaction. IL-10 protein expression in peripheral blood lymphocytes was assessed by standard enzyme-linked immunoassay in 32 patients with renal cancer. RESULTS: Patient-to-control comparisons identified the AA genotype to be significantly greater in patients with renal cell carcinoma (44% vs 30%, p <0.05). However, study of IL-10 protein expression in peripheral blood lymphocytes from patients with renal cancer showed no statistical difference in IL-10 expression among the GG, AA or AG genotypes. CONCLUSIONS: We found that there was a significantly larger proportion of patients with renal cell carcinoma with the AA homozygous genotype than in a normal population cohort. This result is in accordance with those in previous studies of prostate cancer and cutaneous malignant melanoma. In contrast to previous studies of other tumor types, no correlation could be established between IL-10-1082 polymorphism and serum IL-10.     

Impact of cytokine gene polymorphism on cardiovascular risk in renal transplant recipients

Cardiovascular events are the leading causes of morbidity and mortality in renal transplant recipients (RTR). Given the role of inflammation in atherosclerosis, the contribution of functional polymorphisms of cytokines to cardiovascular diseases (CVD) was assessed in RTR in this study. Polymorphisms of tumour necrosis factor alpha (TNF-alpha) gene [-308 (G-->A), -238 (G-->A)], interleukin-10 (IL-10) gene [-1082(A-->G), -819 (T-->C), -592 (A-->C)], transforming growth factor beta 1 (TGF-beta1) gene [codon 10 (T-->C), codon 25 (G-->C)], carotis intima media thickness (CIMT), left ventricular mass index (LVMI), 24-h ambulatory blood pressure and serum lipoprotein homocysteine level, erythrocyte sedimentation rate, serum C-reactive protein (CRP) and serum fibrinogen level of RTR were determined. Seventy-two RTR (26 cadaveric allograft, 46 living-related allograft, 43 male, 29 female) were included in this study. LVMI were similar in TNF-alpha, IL-10 and TGF-beta1 genotypes. Right and left CIMT were higher in TT genotype (n = 16) than CT (n = 46) and CC (n = 10) genotypes of TGF-beta1 codon 10 (T-->C) gene polymorphism (RCIMT, 7.7 +/- 2.2 mm vs. 7.0 +/- 1.4 mm vs. 5.9 +/- 1.4 mm, P = 0.025; LCIMT, 8.5 +/- 2.5 mm vs. 7.0 +/- 1.3 mm vs. 6.1 +/- 1.2 mm, P = 0.002). Lipoprotein (a) level of TT genotype (35.5 +/- 22.5 mg/dl) was higher than CC (4.1 +/- 2.8 mg/dl) and CT (20.4 +/- 11.2 mg/dl) genotypes of TGF-beta1 codon 10 (T-->C) gene polymorphism (P = 0.037). High producers of cytokine IL-10 -1082 [GG (n = 22) vs. AA + AG (n = 50)] and low producers of TGF-beta codon 25 [GC + CC (n = 17) vs. GG (n = 55)] had lower IMT of carotid artery but the difference did not reach statistical significance (P > 0.05). The CIMT of renal transplant patients was similar in IL-10 (-819, -592) and TNF-alpha (-308, -238) genotypes. No difference was observed in 24-h ambulatory blood pressure levels, serum lipoproteins, plasma homocysteine level, erythrocyte sedimentation rate, serum CRP, serum fibrinogen level in IL-10, TNF-alpha and TGF-beta1 genotypes. Besides the well-known factors, TGF-beta1 gene polymorphisms might play a role in CVD in RTR even at early stages of asymptomatic atherosclerosis.     

Hemodialysis procedure does not affect the levels of sICAM-1 and sVCAM-1 in patients with end stage renal disease

Atherosclerosis is by far the leading cause of mortality and morbidity in patients with end stage renal disease undergoing chronic hemodialysis (HD). Vascular endothelial cell adhesion molecules like the intercellular adhesion molecule-1 (ICAM-1) and the vascular cell adhesion molecule-1 (VCAM-1) are involved in the pathogenesis of atherosclerosis. Their soluble forms (sICAM-1, sVCAM-1) are considered potential serum markers of endothelial activation and atherosclerosis. The aim of this study was to clarify the influence of the HD procedure on the levels of sICAM-1 and sVCAM-1 in patients with end stage renal disease. We evaluated 35 clinically stable patients (18 males, 17 females, mean age 61 +/- 12) on chronic HD treatment. Diabetes mellitus coexisted in eight patients and arterial hypertension in 23 patients. Blood was drawn before, every hour during, and after a single HD session in each patient. Low-flux cuprophane dialyzers (GFS 12, Gambro, Lund, Sweden) were used in 22 and high-flux polysulfone dialyzers (Hemoflow F 60S, Fresenius, Oberursel, Germany) in 13 cases. At 30 min into the HD session (n=31, 20 low-flux HD, 11 high-flux HD) blood was drawn simultaneously from the entrance and the exit line of the dialyzer. From all these samples, serum concentrations of sICAM-1 and sVCAM-1 were determined by commercially available enzyme immunoassays (ELISA, R&D Systems, Minneapolis, USA). Results were corrected according to hemoconcentration, where appropriate. Plasma levels of sVCAM-1 were elevated in patients with end stage renal disease before the beginning of the dialysis session when compared to healthy controls (1449 +/- 497 ng/mL vs. 691 +/- 118 ng/mL). On the contrary, such an elevation was not found in the case of sICAM-1 (231 +/- 58.5 ng/mL vs. 236.4 +/- 96.8 ng/mL in healthy controls). These levels remained stable in all measurements throughout the dialysis procedure. Furthermore, serum sICAM-1 and sVCAM-1 levels remained unaltered after the passage of the dialyzer. The levels of sICAM-1 and sVCAM-1 were not influenced by the existence of diabetes mellitus, hypertension, or by the utilization of biocompatible, high flux dialyzers. Our study confirms that in chronic HD patients serum levels for sVCAM-1 are elevated. The levels of adhesion molecules are not affected by the HD procedure. These findings probably can be attributed to a decreased renal clearance or catabolism of sICAM-1 and sVCAM-1 and to the different sources of the two molecules. Neither coexisting diabetes mellitus nor arterial hypertension influences the circulating levels of these adhesion molecules. The functional role of sVCAM-1 and sICAM-1, the exact renal contribution to their metabolism, and their role as markers of atherosclerosis in chronic renal disease need further evaluation.     

The effect of viable Chlamydia pneumoniae on serum cytokines and adhesion molecules in hemodialysis patients

BACKGROUND: Chlamydia pneumoniae (Cp) induces the production of cytokines and adhesion molecules in infected host eukaryotic cells. The causes for pro-inflammatory cytokine and adhesion molecule increase in hemodialysis (HD) patients have not been fully elucidated. The possibility that, in this particularly atherosclerotic population, Cp, a microorganism implicated in the infectious-based inflammatory hypothesis of atherosclerosis' is also responsible for these molecules' increase is assessed in this study. METHODS: In 130 stable HD patients, serum interleukin-1 beta (IL-1), interleukin-6, tumor necrosis factor alpha, interleukin-10, L-selectin, E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 (VCAM-1) levels were determined. Cp presence was identified by inoculation of the patient's peripheral blood mononuclear cells (PBMCs) in Hep-2 cell lines and subsequent polymerase chain reaction (PCR) in DNA extracted from cell cultures, as well as by determination of serum IgG antibodies against Cp (IgGCp). RESULTS: Patients, positive or negative for IgGCp, had no statistically significant differences in all molecules measured. Patients with viable Cp in PBMCs had higher serum levels of IL-1 and soluble VCAM-1 than negative ones for IgGCp (IL-1 6.87 +/- 7.35 vs. 2.34 +/- 1.47 pg/mL; P = 0.0009 and VCAM-1 1647.16 +/- 513.64 vs. 1162.14 +/- 546.83 ng/mL; P = 0.0115, respectively). Viable Cp in PBMCs remained a significant predictor factor for IL-1 and VCAM-1 in statistical analysis, when patients' characteristics and dialysis conditions were also evaluated. CONCLUSIONS: Our results showed that some serum cytokine and adhesion molecule increase in HD patients could be attributed to viable Cp presence in PBMCs. These findings support the Cp-based inflammatory atherogenous hypothesis and add a better understanding of these molecules' increase in HD patients.     

Increased levels of soluble TNF-alpha receptors and cellular adhesion molecules in patients undergoing bioincompatible hemodialysis

BACKGROUND: The study aimed to differentiate the effects of hemodialysis (HD) and chronic renal failure (CRF) on the levels of circulating tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha receptors p55 and p75, soluble vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), soluble endothelial-leukocyte adhesion molecule-1 (sE-selectin) and sP-selectin in 18 patients on regular HD treatment with cuprophane membrane in relation to 15 non-dialyzed CRF patients and 15 healthy controls. METHODS: The serum concentrations were determined with standard ELISA assays. RESULTS: Blood serum p75 and p55 were approximately tenfold increased in CRF (36.7 +/- 6.2 and 27.1 +/- 5.6 ng/ml) and HD patients (45.6 +/- 18.4 and 28.7 +/- 5.9 ng/ml) before the HD session (HD 0), during (HD 20) the session (45.7 +/- 18.4 and 28.5 +/- 7.3 ng/ml) and after (HD 240) the HD session (52.1 +/- 17.4 and 30.9 +/- 8.2 ng/ml) in comparison to control values (5.6 +/- 1.3 and 2.4 +/- 0.8 ng/ml, respectively) (p < 0.01). The highest increment of p75 at the end of HD session (HD 240) was also significantly higher than at preceding time points (HD 0 and 20) (p < 0.05). However, the remaining study parameters did not change during an HD session. Also, there were no relevant changes in TNF-alpha levels if (HD 0) 22.7 +/- 21.5 ng/ml and (HD 240) 21.1 +/- 18.9 ng/ml were compared. Chronic HD status was related to the increase of sVCAM-1 and sICAM-1 levels. Prior to HD, T0 sVCAM-1 and sICAM-1 concentrations were 2,180.4 +/- 761.8 and 567.3 +/- 218.8 ng/ml, during HD (T20): 2,172.7 +/- 759.2 and 602.3 +/- 379.9 ng/ml, and after HD (T240): 2,401.6 +/- 756.4 and 648.3 +/- 183.5 ng/ml, respectively (p < 0.05 vs. controls and CRF patients). sVCAM-1 and sICAM-1 serum levels (1,262.2 +/- 472.9 and 165.6 +/- 50.4 ng/ml) were similar in CRF patients and healthy controls (854.4 +/- 241.5 and 217.6 +/- 74.2 ng/ml, respectively). Even though serum sE- and sP-selectin in CRF patients did not differ from the control (39.8 +/- 21.3 vs. 42.1 +/- 18.9 ng/ml and 187.9 +/- 66.9 vs. 198.8 +/- 62.2 ng/ml, respectively), their levels were increased in HD patients up to 111.9 +/- 54.6 and 453.2 +/- 231.1 ng/ml in patients prior to HD, 118.7 +/- 66.2 and 350.8 +/- 114.8 ng/ml during the HD session and then 132.3 +/- 61.1 and 368.3 +/- 126.6 ng/ml, respectively, after its completion (p < 0.05 in comparison with CRF patients and controls). CONCLUSIONS: The increased circulating TNF-alpha receptors appear more associated with the uremic milieu than HD-related systemic inflammation, whereas increased soluble cellular adhesion molecules in patients undergoing bioincompatible HD may be related to the enhanced systemic inflammation specifically due to maintenance HD.     

Cytokine gene polymorphisms and the inflammatory response to abdominal aortic aneurysm repair

BACKGROUND: Cytokines are key mediators of the inflammatory response to surgery and polymorphic sites in their genes have been shown to affect cytokine production in vitro. The aim of this study was to determine whether cytokine gene polymorphisms affect cytokine production in vivo in patients undergoing abdominal aortic aneurysm (AAA) repair. METHODS: One hundred patients admitted for elective AAA repair had plasma levels of interleukin (IL) 1beta, IL-6, IL-10 and tumour necrosis factor (TNF) alpha measured at induction of anaesthesia and 24 h after operation. Genotypes for each patient were determined using induced heteroduplex genotyping for the following loci: IL-1beta + 3953, IL-6 - 174, IL-10 - 1082/-592 and TNF-alpha - 308. RESULTS: Patients with an IL-10 - 1082 A allele had a significantly higher IL-10 response to surgery than those without an A allele (P = 0.030) and there was also a significant difference in IL-10 response between patients with IL-10 - 1082 AA genotypes and those with GG genotypes (P = 0.030). CONCLUSION: Elective AAA repair results in a measurable cytokine response. In this study the magnitude of this response was not affected by the individual patient's cytokine gene polymorphisms.     

Host Cytokine Genotype is Related to Adverse Prognosis and Systemic Inflammation in Gastro-Oesophageal Cancer

Background Systemic inflammation has been linked with reduced survival in cancer, however, the role of the host cytokine genotype versus tumour phenotype in the generation of this response is not clearly established. This study examined the relationship between cytokine polymorphisms (IL-1β 511, IL-6 174, IL-10 1082, TNFα 308 and LTα +252) and serum cytokine concentrations, serum CRP concentration and survival duration in patients with gastro-oesophageal malignancy. Methods Two hundred and three newly diagnosed patients with gastric or oesophageal cancer had serum CRP and cytokine concentrations determined by ELISA. SNP genotyping was performed by Taqman allelic discrimination genotyping and compared with the genotype observed in 266 healthy volunteers. Clinico-pathological information was collected prospectively and survival duration was recorded. Results Distribution of the cytokine genotypes was similar between patients and controls. The IL-6 174 CC and IL-10 1082 GG genotypes were associated with elevated serum CRP (P = .03, P = .01, respectively; Mann–Whitney U test) and sTNF-R (P = .015, P = .02) concentrations. These genotypes were also associated with reduced survival duration (P = .01, P = .047; log-rank test). TNFα AA genotype was also associated with reduced survival duration on univariate (P = .032) and multivariate analysis (P = .006, multivariate model), but not with inflammatory markers. No other cytokine polymorphisms were associated with systemic inflammatory markers or prognosis. Conclusions There is a pro-inflammatory cytokine haplotype (IL-6 CC, IL-10 GG, TNFα AA) that is associated with adverse prognosis that may act, at least in part, through an inflammatory mediated mechanism. Determining patients’ cytokine haplotype may improve prognostication and allow stratification for intervention studies.     

The impact of donor cytokine gene polymorphisms on the incidence of cytomegalovirus infection after kidney transplantation

Cytomegalovirus (CMV) seronegative recipients of kidneys from CMV seropositive donors are at a high risk of CMV infection after transplantation since viruses in the allograft may reactivate in patients without prior immunity. We hypothesized that the genetic background of the graft has an influence on the incidence of infection. Effects of IL10, IL6 and IFNG gene polymorphisms, known to affect CMV infectivity, were investigated in 71 CMV seronegative recipients of grafts from CMV seropositive cadaver donors. Donor IL10(-1082 AA) genotype reduced the incidence of CMV infection (p=0.031) and CMV episodes in these patients tended to occur later (AA: median 83 days, AG/GG: median 45 days, p=0.072). In multivariate analysis, other explaining factors than the donor IL10(-1082 AA) genotype alone did not improve Cox hazard model (HR=0.3, 95% CI=0.09-0.96, p=0.043). Recipient polymorphisms did not reduce the incidence of CMV infection. We conclude that donor IL10 gene polymorphisms may influence the likelihood of CMV infection in the high risk patients investigated.     

Circulating levels of ICAM-1, VCAM-1, and MCP-1 are increased in haemodialysis patients: association with inflammation, dyslipidaemia, and vascular events.

BACKGROUND: Increased levels of circulating adhesion molecules and chemokines have been reported in haemodialysis (HD) patients but the influence of the HD membranes on their secretion, as well as their pathophysiological implications, remains largely unknown. METHODS: Circulating levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) were measured by immunosorbent assay (ELISA) in 81 HD patients (45 male, mean age 57+/-13 years) and 35 normal subjects. All patients had been stabilized on renal replacement therapy for >3 months and were free of active infection. Thirty-three patients (40.7%) were routinely dialysed with modified cellulose membranes and 48 patients (59.3%) were dialysed with polysulfone membranes. Blood samples were taken directly from the arteriovenous fistula immediately before and at the end of a routine HD session. RESULTS: Pre-dialysis levels were significantly elevated in HD patients compared with controls (ICAM-1 515+/-177 vs 238+/-664 ng/ml, P<0.0001; VCAM-1 2107+/-648 vs 1012+/-115 ng/ml, P<0.0001; MCP-1 427+/-148 vs 125+/-42 pg/ml, P<0.0001). The HD session resulted in a significant increase in the levels of all three molecules measured (515+/-177 vs 679+/-187 ng/ml, P<0.0001; 2107+/-648 vs 2662+/-800 ng/ml, P<0.0001; 427+/-148 vs 567+/-153 pg/ml, P<0.0001, respectively). There was no difference in pre- or post-dialysis levels of the above molecules between patients routinely dialysed with either modified cellulose or polysulfone membranes. MCP-1 levels had a positive correlation with ICAM-1 levels (r=0.41, P<0.0005). VCAM-1 levels had a negative correlation with HDL levels (r=-0.30, P<0.01) and were significantly elevated in patients with HDL <35 mg/dl compared with patients with HDL > or = 35 mg/dl (2300+/-606 vs 1890+/-633 ng/ml, P<0.005). Log-transformed exact C-reactive protein (CRP) values were significantly correlated with ICAM-1 and VCAM-1 levels (r=0.41, P<0.005 and r=0.43, P<0.005, respectively). In addition, compared with patients with normal CRP values, patients with elevated CRP had significantly increased levels of ICAM-1 (466+/-166 vs 580+/-172 ng/ml, P<0.005). Patients with cardiovascular, cerebrovascular, or peripheral vascular diseases had significantly increased serum CRP and ICAM-1 levels compared with patients with no evidence of vascular disease (19.2+/-12.9 vs 7.9+/-11.8 mg/l, P<0.001 and 608+/-189 vs 474+/-155 ng/ml, P<0.005 respectively). CONCLUSIONS: Serum levels of ICAM-1, VCAM-1, and MCP-1 are increased in HD patients and probably result from either inadequate clearance or enhanced synthesis and release. HD session resulted in a significant increase of the above molecule levels but the exact mechanism(s) responsible for these alterations are yet to be fully elucidated. Increased levels of adhesion molecules are associated with inflammation, dyslipidaemia, and cardiovascular events. However, the potential link between these processes and its clinical significance warrants further investigation.     

Analysis of IL-6, IL-10 and IL-17 genetic polymorphisms as risk factors for sepsis development in burned patients

Infection risk, sepsis and mortality after severe burn are primarily determined by patient age, burn size, and depth. Whether genetic differences contribute to otherwise unexpected variability in outcomes is unknown. We sought to determine whether there was an association between IL-6, IL-10 and IL-17 polymorphisms with cytokine production and development of sepsis. We evaluated 71 patients with burns ≥15% TBSA and 109 healthy subjects. The genotypes of IL-6 (-174C/G), IL-10 (-819C/T and -1082A/G) and IL-17 (7488T/C) polymorphisms were identified applying polymerase chain reaction protocols. The cytokine levels in serum were determined with enzyme-linked immunoabsorbent assays. Our results demonstrated no significant differences in the genotype frequencies studied between burn patients and healthy subjects. No significant associations were found among IL-6 and IL-17F genotypes and the related cytokine serum levels. Only IL-10 promoter -1082GG genotype was related to an increased IL-10 production in burned patients. In addition, septic subjects bearing -1082G/G genotype have shown the highest and non-septic bearing -1082A/* genotypes the lowest IL-10 serum levels. All together these data seem to indicate that genetically determined individual difference in IL-10 production might influence the susceptibility to septic complications in burned patients and suggest that these markers might be useful in burned patient management.     

Nonimmunologic complications and gene polymorphisms of immunoregulatory cytokines in long-term renal transplants

BACKGROUND: While the influence of cytokine gene polymorphisms on immunologic complications after organ transplantation is widely evaluated, little is known about predictive value of cytokine genotype for the development of nonimmunologic post-transplant complications: hypertension, dyslipoproteinemia, diabetes mellitus, hyperuricemia. METHODS: The -1082IL-10, -308TNF-alpha, transforming growth factor-beta1 (TGF-beta1) (codon 10, 25), -174IL-6, +874IFN-gamma gene single nucleotide polymorphisms (SNP) were studied in 278 long-term renal transplants by polymerase chain reaction-sequence specific primer (PCR-SSP) with respect to nonimmunologic post-transplant complications. RESULTS: Significant association of the TGF-beta (codon 25) GG genotype with hyperuricemia (P= 0.0013) and dyslipoproteinemia (P= 0.0171) was found. The TGF-beta1 (codon 25) CG genotype was detected more frequently in patients with normal uric acid levels. The +874IFN-gamma AA genotype was associated with type 2/steroid-induced diabetes (P= 0.0127). Frequency of the -1082IL-10 AG genotype was significantly higher in hyperuricemic patients versus controls (P= 0.0022). No associations of polymorphisms in the tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), TGF-beta codon 10 genes with hyperuricemia, dyslipoproteinemia, or diabetes were detected. We failed to observe significant differences in cytokine genotype distribution between hypertensive and normotensive patients. CONCLUSION: We established an association of particular cytokine genotypes with nonimmunologic post-transplant complications. This supports an idea that assessment of cytokine SNPs may allow more accurate prediction of nonimmunologic complications and appropriate adjustment of pre-emptive treatments in long-term transplant patients.     

The association of promoter gene polymorphisms of the tumor necrosis factor-α and interleukin-10 with severity of lactic acidosis during liver transplantation surgery

Background

Orthotopic liver transplantation (OLT) is a major operation, causing cytokine release and other inflammatory responses that can contribute to postreperfusion syndrome occurrence. During the systemic inflammatory response syndrome, increased lactate levels result from excessive cytokine production despite normal oxygen delivery and carbohydrate metabolism. The goal of the study was to determine the relationship between genetic polymorphisms in interleukin (IL)-10 (−1082G/A) or tumor necrosis factor (TNF)-α (−376 G/A) and lactate levels in patients during OLT surgery.

Patients and Methods

This prospective observational study in 40 consecutive adult patients who underwent OLT documented lactic acid levels at 5 times: Immediately after induction of anesthesia, at the end of the pre-anhepatic phase, at the end of the anhepatic phase, 1 hour after reperfusion, and at the end of surgery. Polymerase chain reaction (PCR; RFLP methodology) was used to examine IL-10 (−1082G/A) and TNF-α (−376 G/A) gene polymorphisms.

Results

Carriers of the IL-10/TNF-α genotype combination GG/GG showed significantly different changes in lactate levels at 1 hour after reperfusion and at the end of surgery. Lactate levels were significantly higher among patients heterozygous for TNF-α (AG genotype) compared with patients homozygous for TNF-α (GG genotype) at same times. In contrast, there was no significant difference among IL-10 polymorphic genotypes (−1082G/A).

Conclusion

Genetic factors play a role in the development of lactic acidosis after OLT. IL-10 (−1082G/A) and TNF-α (−376 G/A) gene polymorphisms could influence the variability of lactate levels after liver transplantation surgery.     

Inflammation markers, adhesion molecules, and all-cause and cardiovascular mortality in patients with ESRD: searching for the best risk marker by multivariate modeling

Inflammation is a major risk factor for mortality and cardiovascular (CV) complications in patients with ESRD. The predictive value of C-reactive protein (CRP) of the main proinflammatory cytokines (IL-1beta, IL-6, IL-18, and TNF-alpha) and of two adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) in 217 dialysis patients was compared. Serum IL-6 and CRP added significant prediction power to the multivariate Cox model of all-cause death, and the gain in the prediction power attributable to IL-6 was approximately two times higher than that of CRP. Patients in the third tertiles of serum IL-6 and CRP had a relative risk of all-cause mortality 2.5 and 1.8 times higher than those in the first corresponding tertiles, and there was no statistical difference between these two relative risks. The gain in prediction power associated with TNF-alpha, IL-beta, IL-18, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 was of small degree (P = NS). Similarly, serum IL-6 added the highest prediction power to the CV death model, and the IL-6 attributable gain was approximately two times higher than that of serum CRP. However, the risk estimate for CV mortality of patients with high serum IL-6 did not differ significantly from that of patients with high serum CRP. IL-6 adds significantly greater predictive power for all-cause and CV death to statistical models based on traditional and nontraditional risk factors in ESRD patients. However, the risk estimate by CRP being reasonably close to that of IL-6, CRP may be a cheap alternative to IL-6 in clinical practice.     

白细胞介素10—1082基因多态性与胃癌遗传易感性的Meta分析

目的系统分析中国人群白细胞介素10—1052（IL-10—1082）基因多态性与胃癌遗传易感性的关系。方法采用Cochrane系统评价方法,检索1966年至2012年Medline、Embase、Cochrane Library、中国生物医学文献数据库（CBM）、中国期刊全文数据库（CJFD）和中国科技期刊全文数据库（CSJD）等数据库,收集IL-10—1052基因多态性与中国人群胃癌易感性的病例对照研究。将纳入研究的胃癌患者作为胃癌组,健康人群作为健康对照组。由2名研究者独立提取数据和进行文献质量评价,综合评价IL-10—1082位点基因型GG与AA、AG与AA及等位基因G与A在中国人胃癌组与健康对照组中是否有差异。采用Q检验和,2对异质性进行定量分析。采用固定或随机效应模型合并数据。计数资料采用优势比（OR）及95％可信区间（95％CI）表示。结果共纳入13篇文献,累计样本量5252例,其中胃癌组患者2077例,健康对照组人群3175例。Meta分析结果显示：携带IL．10—1082基因型GG与AG患者,其胃癌发生风险率高于与携带IL-10—1082基因型AA患者（OR=1．76,95％CI1．33～2．33;OR=2．05,95％CI1．62～2．66,P〈0．05）;IL-10—1082基因型具有等位基因G的患者其胃癌发生风险率高于含等位基因A的患者（OR=1．67,95％CI1．31～2．13,P〈0．05）。结论中国人群IL-10—1082基因型GG、AG及等位基因G与胃癌发生有关。     

白细胞介素10基因多态性及幽门螺杆菌感染与胃癌的相关性研究

目的 探讨白细胞介素10(IL-10)启动子区1082位点的单核苷酸多态性(singlenucleotide polymorphisms,SNP)、不同类型幽门螺杆菌(Hp)感染与甘肃地区胃癌易感性之间的关系.方法 采用聚合酶链反应-限制性片段长度多态(PCR-RFLP)和PCR产物直接测序技术分别检测来自甘肃地区人群137例胃癌患者及与其配比的144例对照个体及131例胃癌癌前病变IL-10-1082A/G基因多态性;采用免疫印迹技术对Hp进行毒株分型.结果 ①对照人群IL-10-1082位点的AA、AG、GG 3种基因型分布频率分别为76.4%、22.2%和1.4%;Hp感染情况为Hp Ⅰ型16.0%、HpⅡ型31.9%、阴性52.1%.②癌前病变组IL-10-1082位点的AA、AG、GG 3种基因型分布频率分别为63.4%、32.8%和3.8%.AG+GG基因型携带频率高于正常对照组(P=0.018),携带IL-10-1082 AG+GG基因型个体癌前病变的发病风险增高到1.87倍.③胃癌组IL-10-1082位点的从、AG、GG 3种基因型分布频率分别为58.4%、35.8%和5.8%;胃癌组IL-10-1082 AG+GG基因型携带频率显著高于正常对照组(P=0.010),携带IL-10-1082 AG+GG基因型个体胃癌的发病风险增高到2.31倍.④以IL-10-1082从基因型并Hp免疫印迹阴性组为对照,AG+GG基因型并Hp免疫印迹阴性个体、AG+GG基因型并Hp感染个体、AG+GG基因型并Hp Ⅰ型感染个体胃癌患病风险增高,其中AG+GG基因型并Hp Ⅰ型感染个体的患病风险显著增高,为对照组的9.73倍.结论 IL-10-1082位点A/G多态性与胃癌的遗传易感性相关.     

Anti-inflammatory interleukin-10 genotype protects dialysis patients from cardiovascular events

BACKGROUND: Inflammatory processes play an important role for the progression of atherosclerosis. This can be studied particularly well in patients with chronic renal failure who are on hemodialysis, as they show systemic inflammation due to uremia and dialysis while suffering from premature mortality secondary to rapidly progressing atherosclerosis. Interleukin (IL)-10 is a regulatory cytokine that limits inflammatory processes. The quantitative production of IL-10 is subject to genetic variation based on polymorphisms in the promoter of its gene. We tested the hypothesis that the IL-10 genotype, by influencing the capacity to compensate for dialysis-induced systemic inflammation, determines the risk for cardiovascular complications. METHODS: Three hundred chronic hemodialysis patients were genotyped for the polymorphic bases at positions -1082 and -819 of the IL-10 promoter sequence. They were prospectively followed for a mean of 20.2 +/- 7.3 months. End-points of the study were major events related to cardiac, cerebrovascular or peripheral artery disease. RESULTS: The -1082A* allele, which is associated with low production of the cytokine IL-10 and elevated markers of systemic inflammation such as C reactive protein, was predictive for a higher cardiovascular morbidity (relative risk for cardiovascular events 2.76, 95% confidence interval 1.31 to 4.17, P = 0.004) compared to the -1082G* genotype. CONCLUSION: The IL-10 genotype influences the risk for cardiovascular events in hemodialysis patients and allows the definition of a high risk group. The data provide further evidence for a causal role of systemic inflammation for progressive atherosclerosis in dialysis patients.     

Is there any relationship between serum levels of interleukin-10 and atherosclerosis in hemodialysis patients?

OBJECTIVE: Cardiovascular complications due to atherosclerosis (AS) are the major cause of mortality in hemodialysis (HD) patients. Inflammation may play an important role in the development of AS. Several studies have demonstrated an association between AS and acute-phase proteins and cytokines in the general population and in HD patients. Interleukin-10 (IL-10) is an anti-inflammatory cytokine. The aim of this study was to compare serum levels of inflammatory and anti-inflammatory indicators in HD patients according to the presence or absence of AS. MATERIAL AND METHODS: A total of 33 HD patients were studied. AS was defined as the presence of plaques as detected by Doppler ultrasonography. The patients were subgrouped according to the presence or absence of plaques. Serum levels of IL-1, -2, -6 and -10, C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-alpha) were measured. Risk factors for AS, such as age, gender, hypertension, hyperlipidemia and duration of HD, were also evaluated. RESULTS: Patients with AS had significantly higher high sensitivity (hs)-CRP and lower IL-10 levels. Blood pressure was also elevated in patients with AS. There was an inverse correlation between CRP and IL-10 levels in patients with AS. CONCLUSION: Patients with AS undergoing HD had low serum levels of the anti-inflammatory cytokine IL-10 and high serum levels of hs-CRP. These results may suggest that limitation of the anti-inflammatory response in atherosclerotic uremic patients is a triggering or contributory factor for AS.     

Uremia-associated immune defect: the IL-10-CRP axis

Unstable atherosclerotic disease is related to systemic inflammation. While this inflammation remains at a subclinical level in otherwise healthy individuals, chronic elevation of pro-inflammatory cytokines is a common feature in patients with end-stage renal disease (ESRD). Current hypotheses on the pathogenetic links between inflammation and atherosclerosis emphasize that cytokine-producing monocytes/macrophages can actively infiltrate atherosclerotic plaques. A high activation level of this cell type may contribute to plaque growth. In the healthy, some 15% to 20% of circulating monocytes may be activated for cytokine production. This percentage is much higher in dialysis patients (50%), which may contribute to the rapid progression of atherosclerosis. Anti-inflammatory mechanisms such as interleukin-10 (IL-10) limit the production of a broad range of pro-inflammatory factors. Animal models, as well as clinical findings, suggest an involvement of this cytokine in the pathogenesis of vascular lesions. In hemodialysis (HD) patients, a protective role of IL-10 against systemic inflammation could be proven. A high interindividual variability in IL-10 production leads to distinct patient groups who can or cannot effectively limit the uremia- and dialysis-induced inflammation. Single nucleotide polymorphisms (SNPs) in the promotor of the IL-10 gene may genetically explain this heterogeneity. The IL-10 genotype strongly influences the range of variation of C-reactive protein (CRP), the most widely used marker of inflammation in dialysis patients. By limiting the inflammatory activation in ESRD patients, the IL-10 genotype is predictive for the risk of cardiovascular disease, meaning that the IL-10 "high-producer" genotype is associated with a lower event rate, and even mortality, than the IL-10 "low-producer" genotype.