Reduced expression of Toll-like receptor 4 contributes to impaired cytokine response of monocytes in uremic patients

Toll-like receptors (TLRs) play a pivotal role in pathogen recognition and subsequent cytokine synthesis by immune cells. Uremic patients have a high infectious morbidity, but it remains unclear if this arises from the defective innate immune responses related to TLRs. We studied TLR4 expression in monocytes and their intracellular cytokine synthesis in response to lipopolysaccharide (LPS) stimulation in 35 predialysis patients with chronic kidney disease (CKD) with or without predisposition to bacterial infections and 16 age-matched controls. Expression of TLR4 in unstimulated peripheral monocytes was determined by staining with anti-TLR4 antibody and analysis with flow cytometry. Monocytes were then stimulated by LPS, labeled with anti-CD14 antibody, and subjected to intracellular cytokine staining and flow cytometry. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-8 synthesis was examined in CD14(+) monocytes. TLR4 expression was constitutively diminished in CKD patients with reduced expression being more severe in those CKD patients who were predisposed to infections. Monocytes from these infection prone CKD patients exhibited significantly reduced synthesis of TNF-alpha, IL-1beta, IL-6, and IL-8 in response to LPS challenge compared with those from control subjects. The intensity of synthesis of each cytokine significantly correlated with TLR4 expression levels in monocytes (P<0.01). The capacity of monocytes to synthesize proinflammatory cytokines was significantly reduced in infection prone CKD patients, and this may possibly be due to the reduced monocyte expression of TLR4. Abnormal TLR4 expression by monocytes may play a role in the susceptibility of such patients to bacterial infections.     

IL-18 Inhibits TNF-α-Induced Osteoclastogenesis Possibly via a T Cell-Independent Mechanism in Synergy with IL-12 In Vivo

It has recently been reported that tumor necrosis factor (TNF)-α has the ability to accelerate osteoclastogenesis. We previously reported that the proinflammatory cytokine interleukin (IL)-18 inhibits TNF-α-mediated osteoclastogenesis in mouse bone marrow cultures. In the present study, the effect of IL-18 on TNF-α-mediated osteoclastogenesis was investigated in vivo. We administered TNF-α with or without IL-18 into the supracalvaria of mice. The number of osteoclasts in the suture of the calvaria was increased in mice administered TNF-α. The number of osteoclasts in mice administered both TNF-α and IL-18 was lower than that in mice administered TNF-α alone. We previously showed that IL-12 and IL-18 synergistically inhibit TNF-α-mediated osteoclastogenesis in vitro. To assess the ability of these two cytokines to synergistically inhibit TNF-α-induced osteoclastogenesis in vivo, mice were administered the two cytokines at doses that did not inhibit osteoclast formation. The combination of IL-12 and IL-18 markedly inhibited TNF-α-induced osteoclastogenesis in vivo. To evaluate how IL-12 and IL-18 synergistically affect TNF-α-induced osteoclastogenesis, the IL-18 receptor (IL-18R) and IL-12R expression levels were analyzed by RT-PCR in bone marrow cells cultured with IL-12 or IL-18. IL-18R mRNA was increased in cells cultured with IL-12, while IL-12R mRNA was increased in cells cultured with IL-18. In addition, IL-18 inhibited TNF-α-induced osteoclastogenesis in mice with T-cell depletion caused by anti-CD4 and anti-CD8 antibodies. The present results suggest that IL-18 may inhibit TNF-α-mediated osteoclastogenesis in vivo via a T cell-independent mechanism.     

Pyostomatitis Vegetans: Cellular Immune Profile and Expression of IL-6, IL-8 and TNF-α

The aim of this study was to investigate the cellular immune profile and the expression of IL-6, IL-8 and TNF-α in tissue biopsies of pyostomatitis vegetans (PV). Working hypothesis was that knowledge of the cellular immune profile and role of mediators such as IL-6, IL-8 AND TNF-alpha may contribute to a better understanding of the pathogenesis of this rare entity. Archival tissues from three patients with clinically and histologically confirmed PV were studied. Analysis of the immune profile of the cellular infiltrate and expression of IL-6 and IL-8 were evaluated by immunohistochemistry. ISH was performed to evaluate the expression of TNF-α. Biopsy tissues from erythema multiforme, recurrent aphthous stomatitis, lichen planus and normal buccal mucosa were analyzed as controls. All patients were affected by multiple mucosal ulcerations and yellow pustules mainly located in the vestibular, gingival and palatal mucosa. Histopathologically, all specimens showed ulcerated epithelium with characteristic intraepithelial and/or subepithelial microabscesses containing abundant eosinophils plus a mixed infiltrate composed of lymphocytes and neutrophils. Cellular immune profile of the inflammatory infiltrate revealed a predominance of T-lymphocytes, mainly of cytotoxic (CD3+/CD8+) phenotype, over B-cells. CD20+ B-lymphocytes were also identified to a lesser degree among the lymphoid cells present in the lamina propria. Overexpression of IL-6 and TNF-α was found in both epithelial and inflammatory mononuclear cells. IL-8 expression was shown in the mononuclear cells scattered among the inflammatory infiltrate. Similar findings of overexpression of IL-6, IL-8 and TNF-α were, however, found in control tissues. In PV lesions, the inflammatory infiltrate shows a predominance of cytotoxic lymphocytes. Expression of IL-6, IL-8 and TNF-α, although not specific to PV, appears up-regulated thus these cytokines would represent a suitable therapeutic target. However, the complexity of the cytokine network and their numerous functions require further studies in order to confirm our findings.     

Immunologic Human Renal Allograft Injury Associates with an Altered IL-10/TNF-α Expression Ratio in Regulatory B Cells

Human B cells with immunoregulatory properties in vitro (Bregs) have been defined by the expression of IL-10 and are enriched in various B-cell subsets. However, proinflammatory cytokine expression in B-cell subsets is largely unexplored. We examined the cytokine profiles of human PBMCs and found that subsets of CD24^hiCD38^hi transitional B cells (TrBs), CD24^hiCD27⁺ memory B cells, and naïve B cells express IL-10 and the proinflammatory cytokine TNF-α simultaneously. TrBs had the highest IL-10/TNF-α ratio and suppressed proinflammatory helper T cell 1 (Th1) cytokine expression by autologous T cells in vitro more potently than memory B cells did, despite similar IL-10 expression. Whereas neutralization of IL-10 significantly inhibited TrB-mediated suppression of autologous Th1 cytokine expression, blocking TNF-α increased the suppressive capacity of both memory and naïve B-cell subsets. Thus, the ratio of IL-10/TNF-α expression, a measure of cytokine polarization, may be a better indicator of regulatory function than IL-10 expression alone. Indeed, compared with TrB cells from patients with stable kidney graft function, TrBs from patients with graft rejection displayed similar IL-10 expression levels but increased TNF-α expression (i.e., reduced IL-10/TNF-α ratio), did not inhibit in vitro expression of Th1 cytokines by T cells, and abnormally suppressed expression of Th2 cytokines. In patients with graft dysfunction, a low IL-10/TNF-α ratio in TrBs associated with poor graft outcomes after 3 years of follow-up. In summary, these results indicate that B cell–mediated immune regulation is best characterized by the cytokine polarization profile, a finding that was confirmed in renal transplant patients.     

Preoperative high-dose steroid administration attenuates the surgical stress response following liver resection: results of a prospective randomized study

Background/Purpose Major abdominal surgery such as liver resection is associated with an excessive hyperinflammatory response and transient immunosuppression. We investigated the immunomodulating effect of preoperative pulse administration of high-dose methylprednisolone in patients undergoing hepatic resection without pedicle clamping. Methods Twenty patients who underwent hepatic resection were randomized into two groups: a steroid group (n = 10), in which patients were given 30 mg/kg per body weight (BW) methylprednisolone intravenously, and a control group (n = 10), in which patients received a placebo (sodium chloride) infusion. The main outcome parameter to assess systemic stress was the serum plasma level of interleukin-6 (IL-6). To evaluate cell-mediated immune function, human leukocyte antigen-DR (HLA-DR) expression on peripheral blood monocytes and lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) release by peripheral monocytes was measured. Other investigated serum parameters included C-reactive protein (CRP), total bilirubin, alanine aminotransferase (ALT), prothrombin time (PT)-INR, and cytokines such as IL-8 and IL-10 and TNF-α. Postoperative convalescence, complication rate, and length of hospital stay were compared between the groups. Results Postoperative plasma concentrations of IL-6 (days 1 and 2), IL-8 (days 2 and 3), and CRP (days 1–4) were significantly lower in the steroid than in the control group. The total bilirubin concentration was significantly lower on day 6 in the steroid than in the control group. Four hours after surgery, LPS-induced TNF-α secretion was significantly reduced in the steroid group, but it increased rapidly during the following days. HLA-DR, ALT, and PT-INR levels were not different between the two groups. The postoperative hospital stay in the steroid group was significantly lower compared to that in the control group (mean, 10.5 days versus 14.8 days; P < 0.05). No differences were found in the convalescence score or postoperative complication rate. Conclusions Intravenous methylprednisolone administration before hepatic resection significantly reduced systemic inflammatory cytokine release. No adverse effect on immunity was noted due to the methylprednisolone. We found no significant difference in the convalescence score, but a significantly shorter hospital stay in the steroid group. Further studies with more patients are needed to elucidate the clinical impact of preoperative steroid bolus therapy in liver surgery.     

Effect of major abdominal surgery on endotoxin release and expression of Toll-like receptors 2/4

Background  Surgery can cause endotoxemia, and endotoxin aggregates to Toll-like receptors and acts proinflammatory; repetitive endotoxin application can cause tolerance. The objective of the study is to characterize early inflammatory response and expression of TLR2/4 during major abdominal surgery. Materials and methods  A prospective controlled study of 20 patients with elective major abdominal surgery was performed. Blood samples were collected before and at a defined time after surgery. Endotoxemia, capability of plasma to inactivate endotoxin, cytokine release of LPS-stimulated mononuclear cells, quantitative TLR mRNA expression, and plasma concentrations of TNFα, IL-6, C-reactive protein (CRP), α₁-acid glycoprotein, transferrin, and albumin were measured. Results  Surgery caused endotoxemia (p = 0.053), and the capability of plasma to inactivate endotoxin was reduced (p = 0.0002). Two hours postoperatively, the plasma concentrations of TNFα and IL-6 peaked significantly, but the liberation capacity of mononuclear cells for cytokines (TNFα, IL-1β, IL-6) was significantly reduced. The concentration of CRP and α₁-acid glycoprotein peaked 48 h postoperatively, but those of transferrin and albumin were significantly decreased (p < 0.001, respectively). Median mRNA expression of TLR2 and TLR4 of mononuclear cells was not altered, and there was no obvious trend over time. Conclusion  Major abdominal surgery is associated with endotoxemia, reduced capability of plasma to inactivate endotoxin, cytokine kinetics resembling those of healthy man after experimentally given LPS, and substantial acute-phase reaction. The cytokine liberation of mononuclear cells suggests a state of postoperative endotoxin tolerance. Despite these substantial changes, trends in TLR2/4 expression are not obvious.     

Local secretion of TNF-α from the liver does not correlate with endotoxin, IL-6, or organ function in the early phase after orthotopic liver transplantation

Hepatic ischemia/reperfusion leads to an excessive release of proinflammatory cytokines, which promotes local and remote cell damage. The value of cytokine measurement in humans for predicting graft function after orthotopic liver transplantation (OLT) remains unclear. Therefore, in this study, tumor-necrosis-factor-α (TNF-α), interleukin-6 (IL-6), and endotoxin (ET) levels were determined in the blood taken from the hepatic veins of 31 patients who underwent OLT. Peak levels of TNF-α in hepatic venous blood were measured shortly after reperfusion and were significantly higher than concentrations in the systemic circulation. IL-6 concentrations, peaking 90 min after reperfusion, only correlated with postoperative pulmonary dysfunction. ET was detectable in 21 patients, but levels did not correlate with either IL-6 or TNF-α concentrations. Additionally, serum cytokine levels did not correlate with the duration of ischemia or with histological changes seen in liver biopsies. In general, our study suggests that local secretion of cytokines does not predict liver function in the early posttransplant phase. Received: 25 October 1999 Revised: 7 July 2000 Accepted: 22 November 2000     

Cytokine response in the postoperative period after surgical treatment of benign adnexal masses: comparison between laparoscopy and laparotomy

Background Cytokines are the main mediators of the inflammation and the response to trauma. The purpose of the present study was the comparative assessment in sera of patients with benign adnexal masses treated by laparoscopy or laparotomy of the following proinflammatory and anti-inflammatory cytokines: interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), and IL-10 in the early postoperative period. Methods A total of 40 patients with benign adnexal masses were studied; 25 of whom underwent laparoscopy and 15, laparotomy. Blood serum concentration of IL-1β, IL-6, IL-8, TNF-α, and IL-10 were measured by commercially available ELISA assays before and 4 h, 24 h, and 48 h after the operation. Results Concentrations of IL-6 were significantly increased in both groups at 4 h, 24 h, and 48 h after the surgery; levels of IL-10 showed a significant increase 4 h and 24 h after the operation; an increase in IL-1β levels was observed only after laparotomy; no significant variations were observed in serum levels of IL-8; the postoperative increase of IL-1β, IL-6, and IL-10 levels was more pronounced in patients undergoing laparotomy than in those treated laparoscopically; length of the surgical procedure, amount of CO₂ used, tumor diameter, age, and body mass index (BMI) of the patients did not influence the postoperative patterns of the studied cytokines. Conclusions Systemic cytokine response after operations for benign adnexal masses depends on the degree of the surgical trauma, and is less pronounced in patients undergoing laparoscopy.     

Systemic immune dysfunction in pancreatic cancer patients

Background and aims We investigated the immune status in 32 pancreatic cancer patients (PC) in comparison with healthy controls (HC). Materials and methods Using flow cytometry, peripheral blood lymphocytes (PBL) were characterized by the expression of surface markers for T helper cells (CD4), T suppressor cells (CD8), B cells (CD19) and NK cells (CD56). The blastogenic response of PBL was analyzed after stimulation with concavalin A (ConA), phytohemagglutinin (PHA), pokeweed mitogen (PWM) and anti-CD3 antibodies. The serum levels of TNF-α, IL-1β, IL-2, IL-10, IL-12, IL-18, IL-1RA, sIL-2R and TGF-β were determined by ELISA. Results No differences in the distribution of peripheral immunocytes in PC were found, whereas the blastogenic response of peripheral blood lymphocytes (PBL) after stimulation with PHA or anti-CD3 antibodies was significantly decreased in PC. In PC, we found reduced serum levels of IL-2 and significantly elevated levels of TNF-α, TGF-β1, IL-10, IL-2R, IL-1β and IL-1RA. Conclusion These data provide evidence for a systemic immune dysfunction in pancreatic cancer patients characterized by a shift towards a T helper cell type 2 cytokine profile, a significant elevation of substances related to T cell suppression and a reduced blastogenic response to PHA and anti-CD3 antibodies of PBL. Bertram Poch and Errki Lotspeich contributed equally to this paper.     

Oxidative stress, inflammation and early cardiovascular damage in children with chronic renal failure

The relationship between inflammation, oxidant stress and cardiovascular damage in children with chronic renal failure (CRF) has not previously been investigated. The aim of this study was to investigate markers of oxidative stress, inflammation and early cardiovascular abnormalities. Therefore, erythrocyte superoxide dismutase (SOD) and catalase (CAT) activities; blood glutathione (GSH) and serum malondialdehyde (MDA) levels; C-reactive protein (CRP) and proinflammatory cytokines (IL-6, TNF-α,); and left ventricular masses (LVM) and intima media thicknesses (IMT) were measured in children with CRF. A total of 29 children with CRF (19 nondialysis, 10 peritoneal dialysis) were included. The control group consisted of 25 healthy subjects. CRF children had significantly increased IL-6, TNF-α, CRP and MDA concentrations and decreased SOD, CAT and GSH levels compared with controls (P<0.05). Nondialysis and peritoneal dialysis subgroups had similar oxidative stress and inflammation biomarkers (P>0.05). Erythrocyte CAT was positively correlated with CRP, TNF-α, and IL2-R in the study group. Positive correlations were found between cytokine concentrations, CRP and urea/creatinine levels. Significantly increased LVM and IMT values were found in CRF children (P<0.05). In conclusion, increased oxidant stress and inflammation together with early cardiovascular damage were found in CRF children. Further studies with more patients are needed to verify these results.     

Immunparalyse von T-Lymphocyten und Monocyten in der postoperativen abdominellen Sepsis

In vitro functions of stimulated peripheral T cells and monocytes were investigate in patients experiencing sepsis following major visceral surgery. Cell culture supernatants were analyzed by ELISA for IL-2, IFN-gamma, IL-4, IL-10, TNF-alpha, IL-1 beta, and IL-12p40. In addition, monocyte HLA class II expression was determined by flow cytometry. T cell secretion of IL-2, TNF-alpha, and in part IFN-gamma (but not IL-4) was significantly diminished in non-survivors throughout the entire course of sepsis, compared to controls and sepsis survivors. Production of IL-1 beta and IL-12 p40 by monocytes was strongly reduced in both survivors and non-survivors at the onset of sepsis. Persistence of depressed monocyte cytokine secretion correlated with lethality. Thus, overall suppression of cytokine production by T cells and monocytes was already observed at the beginning of postoperative sepsis. HLA class II expression by monocytes exhibited a strong and sustained down-regulation with no significant differences between sepsis survivors and non-survivors. In summary, suppression of both T cell and monocyte functions develops early during postoperative sepsis. Recovery of immune functions and severity of immune defects are associated with outcome.     

Postoperative suppression of inflammatory cytokines after distal gastrectomy in elderly patients

Purpose  Surgical procedures are being performed on elderly people with increasing frequency, but accordingly, postoperative complications and mortality rates are higher than for younger patients. We conducted this study to establish if cytokine responses after distal gastrectomy in elderly patients differ from those in younger patients. Methods  Twenty-one patients undergoing distal gastrectomy were divided into two groups based on age: the elderly group consisted of 10 patients aged ≥75 years, and the younger group consisted of 11 patients aged <65 years. Blood samples were collected from the patients preoperatively, and then on postoperative days (PODs) 1, 3, and 7, for analysis of interleukin (IL)-6, IL-8, IL-10, soluble tumor necrosis factor receptors (sTNF-R), and IL-1 receptor antagonist (IL-1ra); and also to measure TNF-α and IL-1β after incubation with Escherichia coli lipopolysaccharide. Results  The IL-6 concentration and TNF-α on POD 1 were both significantly lower in the elderly group than in the younger group (P = 0.0058 and P = 0.022, respectively). Conclusion  Cytokine profiles after distal gastrectomy in elderly patients differ from those in younger patients, with lower pro-inflammatory and inflammatory cytokine responses evident in the elderly.     

Human spinal cord injury causes specific increases in surface expression of β integrins on leukocytes

Spinal cord injury (SCI) activates circulating leukocytes that migrate into the injured cord and bystander organs using adhesion molecule-mediated mechanisms. These cells cause oxidative damage, resulting in secondary injury to the spinal cord, as well as injury to bystander organs. This study was designed to examine, over a 6-h to 2-week period, changes in adhesion molecule surface expression on human peripheral leukocytes after SCI (9 subjects), using as controls 10 uninjured subjects and 6 general trauma patients (trauma controls, TC). Both the percentage of cells expressing a given adhesion molecule and the average level of its expression was quantified for both circulating neutrophils and monocytes. The percentage of neutrophils and monocytes expressing the selectin CD62L was unchanged in TC and SCI patients after injury compared to uninjured subjects. Concurrently, the amount of surface CD62L on neutrophils was decreased in SCI and TC subjects, and on monocytes after SCI. The percentage of neutrophils expressing α4 decreased in TC, but not in SCI, subjects. Likewise, the percentage of neutrophils and monocytes expressing CD11d decreased markedly in TC subjects, but not after SCI. In contrast, the mean surface expression of α4 and CD11d by neutrophils and monocytes increased after SCI compared with uninjured and TC subjects. The percentage of cells and surface expression of CD11b were similar in neutrophils of all three groups, whereas CD11b surface expression increased after SCI in monocytes. In summary, unlike changes found after general trauma, the proinflammatory stimulation induced by SCI increases the surface expression of adhesion molecules on circulating neutrophils and monocytes before they infiltrate the injured spinal cord and multiple organs of patients. Integrins may be excellent targets for anti-inflammatory treatment after human SCI.     

右美托咪啶对脂多糖诱导大鼠外周血单核细胞Toll样受体4mRNA表达的影响

目的 探讨右美托咪啶对脂多糖(LPS)诱导大鼠外周血单核细胞Toll样受体4(TLR4)mRNA表达的影响.方法 健康雄性Wistar大鼠40只,取外周血分离培养单核细胞,采用随机数字表法,将其随机分为5组(n=8),A组:阴性对照;B组:单核细胞中加入LPS(终浓度为1μg/ml);C组:单核细胞中加入LPS(终浓度为1μg/ml)+右美托咪啶(终浓度为0.5 ng/ml);D组:单核细胞中加入LPS(终浓度为1μg/ml)+右美托咪啶(终浓度为5.0 ng/ml);E组:单核细胞中加入LPS(终浓度为1μg/ml)+右美托咪啶(终浓度为50.0 ng/ml).孵育24 h后,收集上清液,采用ELISA法测定TNF-α、IL-1β和IL-6的浓度,采用RT-PCR法测定TLR4 mRNA的表达.结果 与A组比较,B组TNF-α、IL-1p、IL-6的浓度升高,TLR4 mRNA表达上调(P＜0.01);与B组比较,C组、D组和E组TNF-α、IL-1β、IL-6的浓度降低,TLR4 mRNA表达下调(P＜0.05或0.01);与C组比较,D组和E组TNF-α、IL-1β、IL-6的浓度降低(P＜0.01),TLR4 mRNA表达差异无统计学意义(P＞0.05);D组和E组各指标比较差异无统计学意义(P＞0.05).结论 右美托咪啶可通过下调TLR4 mRNA表达,抑制TLR4的合成,从而抑制LPS诱导大鼠外周血单核细胞TNF-α、IL-1β和IL-6的生成与释放.

Abstract：

Objective To investigate the effects of different concentrations of dexmedetomidine on the expression of Toll-like receptor 4 (TLR4) mRNA in rat peripheral blood monocytes exposed to lipopolysaccharide ( LPS ). Methods Peripheral blood monocytes isolated from male Wistar rats were seeded in 24-well plate in RPMI 1640 liquid culture medium in CO2 incubator at 37 ℃ and 5% CO2 for 2 h, and were randomly divided into 5 groups ( n = 8 each): group A negative control; group B was exposed to LPS 1 μg/ml and C, D and E groups were exposed to LPS 1 μg/ml + dexmetomidine 0.5, 5.0 and 50.0 ng/ml respectively. The monocytes were then incubated for 24 h. The concentrations of TNF-α, IL-1β and IL-6 in the supernatant of the cultured monocytes were detected by ELISA. The expression of TLR4 mRNA in the monocytes was detected by RT-PCR.Results Exposure to LPS significantly increased the expression of TLR4 mRNA and the concentrations of TNF-α, IL-1β and IL -6 in group B as compared with group A ( P ＜ 0.01 ). Dexmedetomidine attenuated the LPS-induced increase in the expression of TLR 4 mRNA and the concentrations of TNF-α, IL-1β and IL-6 in a dose-dependent manner ( P ＜0.05or 0.01 ). Conclusion Dexmedetomidine can inhibit the synthesis of TLR4 and inhibit the secretion and dilivery of TNF-α, IL-1β and IL-6 by down-regulating the gene expression of TLR4 in rat peripheral blood monocytes exposed to LPS.     

Serum insulin-like growth factor-binding protein 2 levels as an indicator for disease severity in enterohemorrhagic Escherichia coli induced hemolytic uremic syndrome

BackgroundInsulin-like growth factor-binding protein (IGFBP) 2 plays an important role in the regulation of cell adhesion, migration, growth, and apoptosis. This study aimed to investigate the clinical significance of serum IGFBP2 as a biomarker for disease activity and severity in hemolytic uremic syndrome (HUS) induced by enterohemorrhagic Escherichia coli (EHEC).MethodsIGFBP2 production by human renal glomerular endothelial cells (RGECs) after exposure to Shiga toxin 2 (Stx-2) was investigated in vitro. Serum IGFBP2 levels in blood samples obtained from 22 patients with HUS and 10 healthy controls (HCs) were quantified using an enzyme-linked immunosorbent assay. The results were compared to the clinical features of HUS and serum tau and cytokine levels.ResultsStx-2 induced the production of IGFBP2 in RGECs in a dose-dependent manner. Serum IGFBP2 levels were significantly higher in patients with HUS than in HCs and correlated with disease severity. Additionally, serum IGFBP2 levels were significantly higher in patients with encephalopathy than in those without encephalopathy. A serum IGFBP2 level above 3585 pg/mL was associated with a high risk of encephalopathy. Furthermore, serum IGFBP2 levels significantly correlated with serum levels of tau and inflammatory cytokines associated with the development of HUS.ConclusionsCorrelation of serum IGFBP2 level with disease activity in patients with HUS suggests that IGFBP2 may be considered as a possible indicator for disease activity and severity in HUS. Larger studies and additional experiments using various cells in central nervous system should elucidate the true value of IGFBP2 as a clinical diagnostic marker.AbbreviationsIGFBP: insulin-like growth factor-binding protein; HUS: hemolytic uremic syndrome; EHEC: enterohemorrhagic Escherichia coli; RGECs: renal glomerular endothelial cells; STx-2: Shiga toxin 2; HCs: healthy controls; LPS: lipopolysaccharide; ROC: receiver operating characteristic; sTNFR: soluble tumor necrosis factor receptor.     

Perioperative cardiovascular system failure in South Asians undergoing cardiopulmonary bypass is associated with prolonged inflammation and increased Toll-like receptor signaling in inflammatory monocytes

Background

South Asian ethnicity is an independent risk factor for mortality after coronary artery bypass. We tested the hypothesis that this risk results from a greater inflammatory response to cardiopulmonary bypass (CPB).

Methods

This was a single-site prospective cohort study. We compared the inflammatory response to CPB in 20 Caucasians and 17 South Asians undergoing isolated coronary artery bypass grafting surgery.

Results

Plasma levels of proinflammatory cytokines (interleukin [IL]-6, IL-8, IL-12, interferon gamma, and tumor necrosis factor) and anti-inflammatory mediators (IL-10 and soluble TNF receptor I) were measured. The Toll-like receptor (TLR) signaling pathway was examined in peripheral blood monocytes by flow cytometry, measuring surface expression of TLR2, TLR4, and coreceptor CD14 and activation of downstream messenger molecules (interleukin-1 receptor-associated kinase 4, nuclear factor kappa from B cells (NF-κB), c-Jun amino-terminal kinase, p38 mitogen-activated protein kinase, and Protein Kinase B). South Asians had persistently higher plasma levels of IL-6 and exhibited increased TLR signaling through the p38 mitogen-activated protein kinase and Protein Kinase B pathways in inflammatory monocytes after CPB. This increased inflammatory response was paralleled clinically by a higher sequential organ failure assessment score (5.1 ± 1.4 versus 1.5 ± 1.6, P = 0.027) and prolonged cardiovascular system failure (23.5% versus 0%) 48 h after CPB.

Conclusions

South Asians develop an exacerbated systemic inflammatory response after CPB, which may contribute to the higher morbidity and mortality associated with coronary artery bypass in this population. These patients may benefit from targeted anti-inflammatory therapies designed to mitigate the adverse consequences resulting from this response.