Severe acute pancreatitis (SAP) develops in about 25% of patients with acute pancreatitis (AP). Severity of AP is linked to the presence of systemic organ dysfunctions and/or necrotizing pancreatitis pathomorphologically. Risk factors determining independently the outcome of SAP are early multi-organ failure, infection of necrosis and extended necrosis (>50%). Up to one third of patients with necrotizing pancreatitis develop in the late course infection of necroses. Morbidity of SAP is biphasic, in the first week strongly related to early and persistence of organ or multi-organ dysfunction. Clinical sepsis caused by infected necrosis leading to multi-organ failure syndrome (MOFS) occurs in the later course after the first week. To predict sepsis, MOFS or deaths in the first 48-72 h, the highest predictive accuracy has been objectified for procalcitonin and <em>IL</em>-8; the Sepsis-Related Organ Failure Assessment (SOFA)-score predicts the outcome in the first 48 h, and provides a daily assessment of treatment response with a high positive predictive value. Contrast-enhanced CT provides the highest diagnostic accuracy for necrotizing pancreatitis when performed after the first week of disease. Patients who suffer early organ dysfunctions or at risk of developing a severe disease require early intensive care treatment. Early vigorous intravenous fluid replacement is of foremost importance. The goal is to decrease the hematocrit or restore normal cardiocirculatory functions. Antibiotic prophylaxis has not been shown as an effective preventive treatment. Early enteral feeding is based on a high level of evidence, resulting in a reduction of local and systemic infection. Patients suffering infected necrosis causing clinical sepsis, pancreatic abscess or surgical acute abdomen are candidates for early intervention. Hospital mortality of SAP after interventional or surgical debridement has decreased in high volume centers to below <em>20</em>%.

OBJECTIVE

To evaluate the relationship between the severity of necrotizing enterocolitis (NEC) and circulating concentrations of proinflammatory cytokines interleukin (IL)-1beta and IL-8 and counterinflammatory cytokines IL-1 receptor antagonist (IL-1ra) and IL-10. These cytokines have been associated with bowel injury or inflammation and may be released more slowly or later than previously examined cytokines. Also, to determine if any one of these cytokines will predict the eventual severity of NEC when measured at symptom onset.

METHODS

Serial blood samples at onset, 8, 24, 48, and 72 hours were obtained from newborn infants with predefined signs and symptoms of NEC. Normal levels were defined from weight-, gestation-, and age-matched controls. Concentrations of the four cytokines were determined by enzyme-linked immunosorbent assay and compared throughout the time period by stage of NEC, using sepsis as a co-factor. Mean concentrations of each cytokine at onset were compared with the controls. Threshold values were obtained with the best combination of high sensitivity and high specificity for defining stage 1 NEC or for diagnosing stage 3 NEC at onset.

RESULTS

There were 12 cases of stage 1, 18 cases of stage 2, and 6 cases of stage 3 NEC included in the study, as well as 20 control infants. Concentrations of IL-8 and IL-10 were significantly higher in infants with stage 3 NEC from onset through 24 hours compared with infants with less severe NEC. At onset, concentrations of all four cytokines were significantly higher in stage 3 NEC. To identify, at onset, the infants with a final diagnosis of stage 3 NEC, an IL-1ra concentration of >130 000 pg/mL had a sensitivity of 100% and a specificity of 92%. At 8 hours, an IL-10 concentration of >250 pg/mL had a sensitivity of 100% and a specificity of 90% in identifying stage 3 NEC in infants with symptoms suggestive of NEC at onset.

CONCLUSIONS

The severity of NEC and its systemic signs and symptoms are not due to a deficiency of counterregulatory cytokines. In fact, mean concentrations of IL-1ra in NEC are higher than what has been reported in other populations. The cytokines IL-8, IL-1ra, and IL-10 are released later or more slowly after a stimulus and may be more useful in identifying, within hours of symptom onset, which infant will develop significant NEC.

The secretion of <em>IL</em>-2 is a critical and early landmark in the activation program of CD4(+) T cells in vitro, but the lack of sensitive assays has limited its application for studying T cell activation in vivo. Using a mouse cytokine capture assay we were able to detect the rapid secretion of <em>IL</em>-2 after an in vivo stimulus by 1-2 h in naive T cells and as early as 30 min in memory T cells. Maximal secretion was achieved within 1-2 h for memory cells or 6-8 h for naive T cells. Surprisingly <em>IL</em>-2 production terminated quickly in vivo and secretion was undetectable by <em>20</em>-24 h in either cell type. We further demonstrated that this short duration of secretion can be influenced by cellular competition between Ag-specific CD4(+) T cells. The consequences of competition were mimicked by reducing the strength of the antigenic stimulus. These data argue that early competition between T cells influences both the eventual frequency of <em>IL</em>-2 producers in the population and also the duration of their secretion, potentially by altering the strength or duration of the stimulus available to each T cell.

BACKGROUND

Procalcitonin (PCT) concentration increases in bacterial infections but remains low in viral infections and inflammatory diseases. The change is rapid and the molecule is stable, making it a potentially useful marker for distinguishing between bacterial and viral infections.

METHODS

PCT concentration was determined with an immunoluminometric assay on plasma collected at admission in 360 infants and children hospitalized for bacterial or viral infection. It was compared with C-reactive protein (CRP), interleukin 6 and interferon-alpha measured on the same sample.

RESULTS

The mean PCT concentration was 46 microg/l (median, 17.8) in 46 children with septicemia or bacterial meningitis. PCT concentration was>> 1 microg/l in 44 of 46 in this group and in 59 of 78 children with a localized bacterial infection who had a negative blood culture (sensitivity, 83%). PCT concentration was>> 1 microg/l in 16 of 236 children with a viral infection (specificity, 93%). PCT concentration was low in 9 of 10 patients with inflammatory disease and fever. A CRP value>> or =<em>20</em> mg/l was observed in 61 of 236 patients (26%) with viral infection and in 105 of 124 patients (86%) with bacterial infection. <em>IL</em>-6 was>> 100 pg/ml in 14% of patients infected with virus and in 53% with bacteria. A secretion of interferon-alpha was found in serum in 77% of viral infected patients and in 8.6% of bacterial infected patients.

CONCLUSIONS

In this study a PCT value of 1 microg/l or greater had better specificity, sensitivity and predictive value than CRP, interleukin 6 and interferon-alpha in children for distinguishing between viral and bacterial infections. PCT values are higher in invasive bacterial infections, but the cutoff value of 1 microg/l indicates the severity of the disease in localized bacterial infection and helps to decide antibiotic treatment in emergency room. PCT may be useful in an emergency room for differentiation of bacterial vs. viral infections in children and for making decisions about antibiotic treatments.

Human herpesvirus-8 (HHV-8) is a gammaherpesvirus that is present primarily in a state of low level persistence in primary effusion lymphoma cell lines. Using BCBL-1 cells that harbour HHV-8 but lack Epstein-Barr virus, we demonstrate that sodium butyrate is much more effective than the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) at inducing high levels of class II and III virus transcription and viral DNA replication, but also initiates apoptosis. Apoptosis occurs prior to assembly of virions when high concentrations of butyrate (1-3 mM) are used, whereas reduction of butyrate concentration to 0.3 mM decreases the rate of apoptosis and results in production and secretion of enveloped virions that are visualized at high number by electron microscopy in approximately <em>20</em>% of BCBL-1 cells. Butyrate induces much higher levels of multiple class II and class III transcripts than does TPA, including v-MIPI, v-<em>IL</em>-6, v-Bcl-2, vGPCR and ORF26. A decrease in concentration of butyrate from 3 to 0.3 mM delays the peak induction of these genes, but peak levels remain higher than peak levels in response to TPA. These studies indicate that the massive apoptosis induced by 3 mM butyrate could be diminished and delayed by reduction of butyrate concentration to 0.3 mM, thereby allowing expression of high levels of lytic-associated genes and production of high yields of HHV-8 virions.

Chronic inflammation and oxidative stress have been implicated in the pathophysiology of Major Depressive Disorder (MDD), as well as in a number of chronic medical conditions. The aim of this study was to examine the relationship between peripheral inflammatory and oxidative stress markers in un-medicated subjects with MDD compared to non-depressed healthy controls and compared to subjects with MDD after antidepressant treatment. We examined the relationships between <em>IL</em>-6, <em>IL</em>-10, and the <em>IL</em>-6/<em>IL</em>-10 inflammatory ratio vs. F2-isoprostanes (F2-IsoP), a marker of oxidative stress, in un-medicated MDD patients (n=<em>20</em>) before and after 8 weeks of open-label sertraline treatment (n=17), compared to healthy non-depressed controls (n=<em>20</em>). Among the un-medicated MDD subjects, F2-IsoP concentrations were positively correlated with <em>IL</em>-6 concentrations (p<0.05) and were negatively correlated with <em>IL</em>-10 concentrations (p<0.01). Accordingly, F2-IsoP concentrations were positively correlated with the ratio of <em>IL</em>-6/<em>IL</em>-10 (p<0.01). In contrast, in the control group, there were no significant correlations between F2-IsoPs and either cytokine or their ratio. After MDD subjects were treated with sertraline for 8 weeks, F2-IsoPs were no longer significantly correlated with <em>IL</em>-6, <em>IL</em>-10 or the <em>IL</em>-6/<em>IL</em>-10 ratio. These data suggest oxidative stress and inflammatory processes are positively associated in untreated MDD. Our findings are consistent with the hypothesis that the homeostatic buffering mechanisms regulating oxidation and inflammation in healthy individuals become dysregulated in untreated MDD, and may be improved with antidepressant treatment. These findings may help explain the increased risk of comorbid medical illnesses in MDD.

Psoriasis is a chronic skin disease that affects about 1.5% of the Caucasian population and is characterized by typical macroscopic and microscopic skin alterations. Psoriatic lesions are sharply demarcated, red and slightly raised lesions with silver-whitish scales. The microscopic alterations of psoriatic plaques include an infiltration of immune cells in the dermis and epidermis, a dilatation and an increase in the number of blood vessels in the upper dermis, and a massively thickened epidermis with atypical keratinocyte differentiation. It is considered a fact that the immune system plays an important role in the pathogenesis of psoriasis. Since the early 1990s, it has been assumed that T1 cells play the dominant role in the initiation and maintenance of psoriasis. However, the profound success of anti-tumor necrosis factor-alpha therapy, when compared with T-cell depletion therapies, should provoke us to critically re-evaluate the current hypothesis for psoriasis pathogenesis. Recently made discoveries regarding other T-cell populations such as Th17 and regulatory T cells, dendritic cells, macrophages, the keratinocyte signal transduction and novel cytokines including interleukin (<em>IL</em>)-22, <em>IL</em>-23 and <em>IL</em>-<em>20</em>, let us postulate that the pathogenesis of psoriasis consists of distinct subsequent stages, in each of them different cell types playing a dominant role. Our model helps to explain the varied effectiveness of the currently tested immune modulating therapies and may enable the prediction of the success of future therapies.

A family of interleukin-10 (<em>IL</em>-10)-related cytokines has emerged, comprising a series of herpesviral and poxviral members and several cellular sequence paralogs, including <em>IL</em>-19, <em>IL</em>-<em>20</em>, <em>IL</em>-22 [<em>IL</em>-10-related T-cell-derived inducible factor (<em>IL</em>-TIF)], <em>IL</em>-24 [melanoma differentiation-associated antigen 7 (MDA-7)] and <em>IL</em>-26 (AK155). Although the predicted helical structure of these homodimeric molecules is conserved, certain receptor-binding residues are variable and define the interaction with specific heterodimers of different type-2 cytokine receptors. This leads, through the activation of signal transducer and activator of transcription (STAT) factors, to diverse biological effects. For example, whereas <em>IL</em>-10 is a well-studied pleiotropic immunosuppressive and immunostimulatory cytokine, <em>IL</em>-22/<em>IL</em>-TIF mediates acute-phase response signals in hepatocytes and <em>IL</em>-<em>20</em> induces the hyperproliferation of keratinocytes, which has been proposed as a pathogenic mechanism of psoriasis.

OBJECTIVE

Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor regressions. The optimal TIL product for ACT is unknown.

METHODS

Patients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8(+)-enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points.

RESULTS

Thirty-four patients received unselected young TILs with a median of 8.0% CD4(+) lymphocytes, and 35 patients received CD8(+)-enriched TILs with a median of 0.3% CD4(+) lymphocytes. One month after TIL infusion, patients who received CD8(+)-enriched TILs had significantly fewer CD4(+) peripheral blood lymphocytes (P = .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors [RECIST]), and seven patients responded to CD8(+)-enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P = .04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8(+)-enriched TILs responded.

CONCLUSIONS

A randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8(+)-enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs.

Circulating CD4+ CD25+ regulatory T cells (Tregs) have been demonstrated to maintain immunotolerance and suppress the antigen-specific or antigen-non-specific T-cell responses, but their role in chronic hepatitis B (CHB) infection in humans has not been well characterized. In this study, we analysed the frequency and phenotypic characteristics of CD4+ CD25+ Tregs in patients of different hepatitis B virus (HBV) infection status, and investigated the effect of Tregs on antiviral immune responses in CHB patients, and the mechanism of this effect. A total of 137 subjects, including 79 CHB patients, 26 asymptomatic HBV carriers (ASCs), 12 acute hepatitis B (AHB) patients and <em>20</em> healthy controls, were enrolled in the study. We found that the frequency of CD4+ CD25(high) Tregs in AHB patients was comparable to that in healthy controls, while it was significantly increased in CHB patients. CD4+ CD25+ Tregs produced interleukin (<em>IL</em>)-10 but little or no interferon (IFN)-gamma under anti-CD3 stimulation. In CHB patients, the frequency of CD4+ CD25(high) Tregs positively correlated with serum viral load, and the Tregs were capable of suppressing the proliferation and IFN-gamma production of autologous peripheral blood mononuclear cells (PBMC) mediated by HBV antigen stimulation in vitro. However, combined administration of anti-programmed death-1 (PD-1) and anti-cytotoxic lymphocyte antigen-4 (CTLA-4) monoclonal antibody slightly enhanced the cellular proliferation and significantly increased the IFN-gamma production of PBMC cocultured with Tregs at a ratio of 2:1. Thus, the frequency of circulating CD4+ CD25+ Tregs is increased in patients with CHB, and this may play an important role in viral persistence by modulating virus-specific immune responses.

Orosomucoid like 3 (ORMDL3) has been strongly linked with asthma in genetic association studies, but its function in asthma is unknown. We demonstrate that in mice ORMDL3 is an allergen and cytokine (<em>IL</em>-4 or <em>IL</em>-13) inducible endoplasmic reticulum (ER) gene expressed predominantly in airway epithelial cells. Allergen challenge induces a 127-fold increase in ORMDL3 mRNA in bronchial epithelium in WT mice, with lesser 15-fold increases in ORMDL-2 and no changes in ORMDL-1. Studies of STAT-6-deficient mice demonstrated that ORMDL3 mRNA induction highly depends on STAT-6. Transfection of ORMDL3 in human bronchial epithelial cells in vitro induced expression of metalloproteases (MMP-9, ADAM-8), CC chemokines (CCL-<em>20</em>), CXC chemokines (<em>IL</em>-8, CXCL-10, CXCL-11), oligoadenylate synthetases (OAS) genes, and selectively activated activating transcription factor 6 (ATF6), an unfolded protein response (UPR) pathway transcription factor. siRNA knockdown of ATF-6α in lung epithelial cells inhibited expression of SERCA2b, which has been implicated in airway remodeling in asthma. In addition, transfection of ORMDL3 in lung epithelial cells activated ATF6α and induced SERCA2b. These studies provide evidence of the inducible nature of ORMDL3 ER expression in particular in bronchial epithelial cells and suggest an ER UPR pathway through which ORMDL3 may be linked to asthma.

Observational studies have linked lower omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and higher omega-6 (n-6) PUFAs with inflammation and depression, but randomized controlled trial (RCT) data have been mixed. To determine whether n-3 decreases proinflammatory cytokine production and depressive and anxiety symptoms in healthy young adults, this parallel group, placebo-controlled, double-blind 12-week RCT compared n-3 supplementation with placebo. The participants, 68 medical students, provided serial blood samples during lower-stress periods as well as on days before an exam. The students received either n-3 (2.5 g/d, <em>20</em>85 mg eicosapentaenoic acid and 348 mg docosahexanoic acid) or placebo capsules that mirrored the proportions of fatty acids in the typical American diet. Compared to controls, those students who received n-3 showed a 14% decrease in lipopolysaccharide (LPS) stimulated interleukin 6 (<em>IL</em>-6) production and a <em>20</em>% reduction in anxiety symptoms, without significant change in depressive symptoms. Individuals differ in absorption and metabolism of n-3 PUFA supplements, as well as in adherence; accordingly, planned secondary analyses that used the plasma n-6:n-3 ratio in place of treatment group showed that decreasing n-6:n-3 ratios led to lower anxiety and reductions in stimulated <em>IL</em>-6 and tumor necrosis factor alpha (TNF-α) production, as well as marginal differences in serum TNF-α. These data suggest that n-3 supplementation can reduce inflammation and anxiety even among healthy young adults. The reduction in anxiety symptoms associated with n-3 supplementation provides the first evidence that n-3 may have potential anxiolytic benefits for individuals without an anxiety disorder diagnosis. ClinicalTrials.gov identifier: NCT00519779.

To study the role of Kupffer cells (KC) as a cellular source of proinflammatory cytokines in hepatic ischemia/reperfusion, Sprague-Dawley rats were subjected to <em>20</em> min global hepatic ischemia. Sham-operated animals served as controls. Blood levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (<em>IL</em>-1 alpha), and interleukin 6 (<em>IL</em>-6) were determined after 10, 30, 60, 1<em>20</em>, and 240 min of reperfusion and compared with spontaneous cytokine release by KC isolated after 60 min of reperfusion. Hepatic ischemia/reperfusion resulted in an enhanced (p < .01) spontaneous release of TNF-alpha (+482%), <em>IL</em>-1 alpha (+33%), and <em>IL</em>-6 (+175%) by KC. Kinetic analysis of cytokinemia revealed an early increase (p < .01) of TNF-alpha and <em>IL</em>-1 alpha within minutes upon reperfusion, while an elevation of <em>IL</em>-6 serum levels was observed with a delay of 2 h. Early cytokinemia was associated with dysfunction/injury of the liver, lung, and kidney after 4 and 24 h of reperfusion, respectively. These data indicate that hepatic ischemia/reperfusion results in Kupffer cell activation and increased cytokine levels, which may produce systemic inflammation and may be responsible for tissue injury locally and on remote sites.

BACKGROUND

The prevalence of both obesity and metabolic syndrome (MetS) is increasing at alarming rates globally. Both predispose to diabetes, cardiovascular disease, fatty liver disease, obstructive sleep apnea, and certain cancers. Understanding the mechanisms contributing to increased cardiometabolic risk in obesity and MetS is of utmost importance.

METHODS

For this review, we performed a detailed literature search on PubMed of all publications related to Toll-like receptors (TLRs) and obesity and MetS for the last <em>20</em> years.

RESULTS

The TLRs are well-characterized immune receptors that enhance inflammation. The recognition of pathogen-associated molecular patterns and endogenous (host-derived) ligands released by various cell types triggers activation and expression of TLRs. TLRs, especially TLR2 and TLR4, induce insulin resistance, which is pivotal in the pathogenesis of obesity and MetS. Both obesity and MetS are characterized by low-grade chronic inflammation, possibly triggered by activation of TLR2 and TLR4. TLRs, especially TLR4, are activated by fatty acids and endotoxinemia (a marker of gut permeability), features of both obesity and MetS, resulting in activation of nuclear factor-κB and increased release of inflammatory biomediators such as IL-6, IL-1β, TNF-α, and monocyte chemotactic protein-1, which play a role in the pathophysiology of obesity and MetS. Reduction of calories, exercise, and nutraceutical and pharmacological agents can modulate TLRs.

CONCLUSIONS

In this review, we present evidence for a pivotal role of TLR-induced inflammation in both obesity and MetS and speculate that targeting these TLRs can forestall their adverse sequelae of diabetes and cardiovascular disease.

BACKGROUND

To develop a scoring method for quantifying nutrition risk in the intensive care unit (ICU).

METHODS

A prospective, observational study of patients expected to stay>> 24 hours. We collected data for key variables considered for inclusion in the score which included: age, baseline APACHE II, baseline SOFA score, number of comorbidities, days from hospital admission to ICU admission, Body Mass Index (BMI) < <em>20</em>, estimated % oral intake in the week prior, weight loss in the last 3 months and serum interleukin-6 (<em>IL</em>-6), procalcitonin (PCT), and C-reactive protein (CRP) levels. Approximate quintiles of each variable were assigned points based on the strength of their association with 28 day mortality.

RESULTS

A total of 597 patients were enrolled in this study. Based on the statistical significance in the multivariable model, the final score used all candidate variables except BMI, CRP, PCT, estimated percentage oral intake and weight loss. As the score increased, so did mortality rate and duration of mechanical ventilation. Logistic regression demonstrated that nutritional adequacy modifies the association between the score and 28 day mortality (p = 0.01).

CONCLUSIONS

This scoring algorithm may be helpful in identifying critically ill patients most likely to benefit from aggressive nutrition therapy.

OBJECTIVE

To determine levels of a panel of inflammatory molecules and matrix metalloproteinases in the tears of patients with keratoconus.

METHODS

A prospective, case-control study.

METHODS

Twenty-eight patients (1 eye from each) diagnosed with keratoconus at the Instituto Galego de Oftalmoloxia, Santiago de Compostela, Spain, during the period from September <em>20</em>01 to June <em>20</em>02, and <em>20</em> normal control subjects (1 eye each) were studied.

METHODS

Patients with keratoconus were examined in a routine fashion, and keratometric readings were taken to monitor the degree of ectasia. Fifteen microliters of tears was collected by capillary flow from each eye.

METHODS

The concentrations of cytokines (interleukin-4 [IL-4], IL-6, IL-10, and tumor necrosis factor alpha [TNF-alpha]), cell adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1), and matrix metalloproteinase 9 (MMP-9) were measured by enzyme-linked immunoadsorbent assay.

RESULTS

Patients with keratoconus initially had significantly higher levels of IL-6 (6.7 [4.8-10.8] pg/ml vs. 2.2 [1.0-4.1] pg/ml in control subjects [P<0.0001]), TNF-alpha (3.8 [2.9-14.4] pg/ml vs. 1.8 [1.5-2.3] pg/ml in control subjects [P<0.0001]), and MMP-9 (66.5 [49.2-139.3]ng/ml vs. 6.1 [3.9-8.3] ng/ml in control subjects. The extent of the increase was found to be associated with the severity of keratoconus.

CONCLUSIONS

Interleukin-6, TNF-alpha, and MMP-9 are overexpressed in the tears of patients with keratoconus, indicating that the pathogenesis of keratoconus may involve chronic inflammatory events.

We investigated serum levels of interleukin (<em>IL</em>)-2, <em>IL</em>-10, <em>IL</em>-6, <em>IL</em>-4, TNFalpha, INFgamma in 7 patients with atypical parkinsonism (AP), 31 idiopathic PD (iPD) patients, 17 idiopathic PD with cardiovascular risk factor (iPD-CVRF) patients, and <em>20</em> age-matched controls (healthy, non-parkinsonian patients). Cytokine concentrations were measured using the Becton Dickinson (BD) human Th1/Th2 Cytokine kit II with a flow cytometry system. The concentrations of <em>IL</em>-2, <em>IL</em>-10, <em>IL</em>-4, <em>IL</em>-6, TNFalpha, and INFgamma were detectable in the serum from all groups, including the control. Increased serum <em>IL</em>-2, <em>IL</em>-10, <em>IL</em>-4, <em>IL</em>-6, TNFalpha, and INFgamma concentrations were found in all groups of parkinsonian patients, as compared to the control group. The highest elevations of serum <em>IL</em>-2, <em>IL</em>-4, <em>IL</em>-6, TNFalpha, and INFgamma concentrations were observed in AP patients, as compared to the iPD and iPD-CVRF groups. However, the serum <em>IL</em>-6 concentration was higher in the iPD-CVRF group than in the iPD group. The <em>IL</em>-10 level was significantly higher in all groups of PD patients relative to the control group, but was the lowest in the serum from the AP patients. Moreover, the serum levels of lipid peroxidation products were enhanced 2.1- and 1.5-fold in AP and both iPD groups, respectively. These results argue in favor of the involvement of immunological events in the process of neurodegeneration in AP and PD.

OBJECTIVE

We aimed to explore the role of interleukin (IL)-1B cluster gene polymorphisms at positions -511, -31, and +3954 and the receptor IL-1RN variable number tandem repeat polymorphisms in the susceptibility to gastric carcinoma through a systematic review and meta-analysis.

METHODS

Each initially included article was scored for quality appraisal. The desirable data were extracted and registered into databases. Studies that deviated from Hardy-Weinberg equilibrium were excluded. Eighteen studies were ultimately eligible for the meta-analysis of <em>IL</em>1B-511, 21 studies for <em>IL</em>1B-31, 10 studies for <em>IL</em>1B+3954, and 20 studies for <em>IL</em>1RN variable number tandem repeat genetic polymorphisms, respectively. Original groups were collapsed and re-grouping was adopted in line with the most probably appropriate genetic models. Potential sources of heterogeneity were sought out via stratification and sensitivity analyses, and biases across studies were estimated.

RESULTS

The pooled odds ratios (95% confidence intervals, P-value) associated with IL-1B -511 T carriers versus CC genotypes and with RN *2 carriers versus L/L were 1.23 (1.04-1.45, P = 0.015) and 1.26 (1.06-1.51, P = 0.010), respectively, for overall gastric carcinoma; 1.31 (1.04-1.64, P = 0.020) and 1.47 (1.21-1.79, P = 0.000), respectively, for non-cardia gastric cancer; 1.55 (1.05-2.28, P = 0.026) and 1.66 (1.23-2.25, P = 0.001), respectively, for intestinal type gastric carcinoma; and 1.33 (1.04-1.71, P = 0.023) and 1.31 (1.07-1.61, P = 0.010), respectively, in Caucasians for overall gastric carcinoma. The pooled odds ratio (95% confidence interval, P-value) regarding IL-1B-31 CC plus TT versus CT was 0.73 (0.60-0.89, P = 0.002) for intestinal type gastric carcinoma. Genotyping methods and publication time could constitute the sources of heterogeneity across studies. Publication biases were not found.

CONCLUSIONS

IL-1B -511 T allele and IL-1 RN *2 VNTR are significantly associated with an increased risk of developing gastric carcinoma and even more significantly with non-cardia gastric carcinoma or with intestinal-type gastric carcinoma. Both are significantly associated with an increased risk of developing gastric carcinoma among Caucasians, but not among Asians or Hispanics.

BACKGROUND

Although adverse effects of severe chronic stress on immunocompetence and physical well-being in older adults have been reported, the immune response to less severe life stress among healthy older adults, particularly among women, is not well understood. Interleukin-6 (IL-6) has been considered a good overall indicator of immune functioning in older adults because of its contribution to the pathogenesis of several age-related conditions such as osteoporosis. Regulation of IL-6 is impaired in elderly adults, and levels of IL-6 increase with stress and depression. This research cross-sectionally examined levels of IL-6 in three groups of healthy older women with varying levels of life stress and mood disturbance and a healthy group of young women.

METHODS

Subjects included 18 caregivers of Alzheimer's patients, 17 older women assessed one month before relocation of their residence, 15 nonmoving and noncaregiving older women, and 20 younger women. Subjects completed the Profile of Mood States (POMS) and had early morning blood draws.

RESULTS

Alzheimer's caregivers reported significantly greater distress than women of all other groups. IL-6 levels in caregivers were significantly higher than those of all other women. The older women had significantly higher IL-6 than young controls, but there were no significant differences in IL-6 between movers and older controls. Among all women, greater depression and distress were related to higher levels of IL-6.

CONCLUSIONS

These findings suggest that in older women, chronic stressors are associated with significant elevations in IL-6 over and above the elevations associated with normal aging, but that moderate stressors may not be related to appreciable elevations in IL-6.

The CXC chemokine <em>IL</em>-8, which promotes adhesion, activation, and transmigration of polymorphonuclear neutrophils (PMN), has been associated with production of tissue injury in reperfused myocardium. Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric peptide that is a key regulator of genes such as heme oxygenase (HO)-1 expressed under hypoxic conditions. We hypothesized that HO-1 plays an important role in regulating proinflammatory mediator production under conditions of ischemia-reperfusion. HIF-1 was activated in the human microvascular endothelial cell line (HMEC-1) with the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG). DMOG significantly attenuated cytokine-induced <em>IL</em>-8 promoter activity and protein secretion and cytokine-induced PMN migration across human microvascular endothelial cell line HMEC-1 monolayers. In vivo studies in a rabbit model of myocardial ischemia-reperfusion showed that rabbits pretreated with a <em>20</em> mg/kg DMOG infusion (n = 6) 24 h before study exhibited a 21.58 +/- 1.76% infarct size compared with 35.25 +/- 2.06% in saline-treated ischemia-reperfusion animals (n = 6, change in reduction = 39%; P < 0.001). In DMOG-pretreated (<em>20</em> mg/kg) animals, plasma <em>IL</em>-8 levels at 3 h after onset of reperfusion were 405 +/- 40 pg/ml vs. 790 +/- 40 pg/ml in saline-treated ischemia-reperfusion animals (P < 0.001). DMOG pretreatment reduced myocardial myeloperoxidase activity, expressed as number of PMN per gram of myocardium, to 1.43 +/- 0.59 vs. 4.86 +/- 1.1 (P = 0.012) in saline-treated ischemia-reperfused hearts. Both in vitro and in vivo DMOG-attenuated <em>IL</em>-8 production was associated with robust HO-1 expression. Thus our data show that HIF-1 activation induces substantial HO-1 expression that is associated with attenuated proinflammatory chemokine production by microvascular endothelium in vitro and in vivo.

The effect of <em>IL</em>-4 on the IFN-gamma-induced state of activation of cultured human monocytes was investigated with regard to their ability to produce hydrogen peroxide and their antileishmanial capacity towards the intracellular parasite Leishmania donovani. <em>IL</em>-4 was found to inhibit the IFN-gamma-dependent hydrogen peroxide production of monocytes. Treatment of monocytes with IFN-gamma (<em>20</em>0 to 600 U/ml) for 48 h increased the hydrogen peroxide production fourfold above background. Coincubation of the monocytes with <em>IL</em>-4 (1 to 1000 U/ml) and IFN-gamma (<em>20</em>0 to 600 U/ml) inhibited this increase by 50 to 100%. <em>IL</em>-4 alone did not modulate the hydrogen peroxide production of monocytes. Pretreatment of monocytes with <em>IL</em>-4 for <em>20</em> min to 3 h was already effective in preventing the IFN-gamma response. Addition of <em>IL</em>-4 not later than 6 h after the start of incubation with IFN-gamma was necessary for an optimal inhibitory effect. <em>IL</em>-4 also inhibited the IFN-gamma-induced antileishmanial capacity of monocytes: IFN-gamma (1000 U/ml) induced a 54 +/- 10% reduction in the number of parasites. Monocytes treated with combinations of <em>IL</em>-4 (100 to 1000 U/ml) and IFN-gamma (1000 U/ml) were unable to reduce the parasite numbers. <em>IL</em>-4 alone did not alter the uptake of Leishmania donovani nor induce antileishmanial activity. These results demonstrate that <em>IL</em>-4 disables human cultured monocytes to respond to IFN-gamma activation.

BACKGROUND

Surgical trauma and anesthesia are known to cause transient postoperative suppression of the immune system. In randomized controlled trials, it has been shown that laparoscopic colorectal resections have short-term benefits not observed with conventional colorectal resections. We hypothesized that these benefits were due to the reduction in surgical trauma, leading to a diminished cytokine response and less depression of cell-mediated immunity after laparoscopy.

METHODS

In a prospective randomized trial, colorectal cancer patients without evidence of metastatic disease underwent either laparoscopic (n = <em>20</em>) or conventional (n = <em>20</em>) tumor resection. Postoperative immune function was assessed by measuring the white blood cell (WBC) count, the CD4+ and CD8+ lymphocytes, the CD4+/CD8+/ratio, and the HLA-DR expression of CD14+ monocytes. In addition, the production of interleukin-6 (<em>IL</em> = 6) and TNF-a were measured after ex vivo stimulation of mononuclear blood cells with lipopolysaccharide (LPS) and compared to the plasma levels of these cytokines. Postoperative mean levels of the immunologic parameters for the two groups were calculated and compared using the Mann-Whitney U test.

RESULTS

Preoperatively, there were no differences between the two groups in terms of patient characteristics or immunologic parameters. Although the postoperative peak concentrations of white blood cells were significant lower in the laparoscopic group than the conventional group (p < 0.05), there were no differences between the two groups in the subpopulation of lymphocytes (CD4+, CD8+). HLA-DR expression of CD14+ monocytes was lower in the conventional group on the 4th postoperative day (p < 0.05). The laparoscopic group showed higher values in cytokine production of mononuclear blood cells after LPS stimulation. Postoperative plasma peak concentrations of IL-6 and TNF-a were lower after laparoscopic resection.

CONCLUSIONS

Postoperative cell-mediated immunity was better preserved after laparoscopic than after conventional colorectal resection. Cellular cytokine production was preserved only in the laparoscopic group, while cytokine plasma levels were significantly higher in the conventional group. These findings may have important implications for the use of laparoscopic colorectal resection, especially in patients with malignant disease.

BACKGROUND

Behçet disease (BD) is a chronic systemic inflammatory disorder of unknown etiology.

OBJECTIVE

To determine the nature of T cells driving inflammatory lesions in BD.

METHODS

T cell homeostasis and cytokines production were analyzed in peripheral blood and brain inflammatory lesions from 45 adult patients with BD (active and untreated BD [n = 25] and patients in remission [n = <em>20</em>]) and <em>20</em> healthy donors, using Luminex, flow cytometry, immunohistochemistry, and immunofluorescence analysis.

RESULTS

We found a marked increase in T(H)17 cells and a decrease in the frequency of CD4(+) forkhead box P3(+) regulatory T cells (Tregs) in peripheral blood that were induced by IL-21 production and that correlate with BD activity. The addition of serum from patients with active BD in a sorted CD4(+) T cells culture of healthy donors induced a significant and dose-dependent production of IL-17A and a decrease in forkhead box P3 expression. We demonstrated the presence of IL-21- and IL-17A-producing T cells within the cerebrospinal fluid, brain parenchyma inflammatory infiltrates, and intracerebral blood vessels from patients with active BD and central nervous system involvement. The stimulation of CD4(+) T cells with IL-21 increased T(H)17 and T(H)1 differentiation and decreased the frequency of Treg cells. Conversely, IL-21 blockade with an IL-21R-Fc restored the T(H)17 and Treg homeostasis in patients with BD.

CONCLUSIONS

We provided here the first evidence of the critical role of IL-21 in driving inflammatory lesions in BD by promoting T(H)17 effectors and suppressing Treg cells. IL-21 represents a promising target for novel therapy in BD.

The glycosylphosphatidylinositol (GPI) anchors of Plasmodium falciparum have been proposed to be the major factors that contribute to malaria pathogenesis by eliciting the production of proinflammatory cytokines and nitric oxide by the host innate immune system. In this study we demonstrate that the parasite GPIs can effectively induce the production of TNF-alpha at 5-<em>20</em> nm concentrations in interferon-gamma-primed monocytes and macrophages. The potency of the parasite GPIs activity is physiologically relevant to their ability to contribute to severe malaria pathogenesis. More importantly, we investigated the requirement of the extracellular signal-regulated kinase (ERK)-, c-Jun N-terminal kinase (JNK)-, p38-, and NF-kappaB-signaling pathways that are activated in response to P. falciparum GPIs through toll-like receptor-mediated recognition (Krishnegowda, G., Hajjar, A. M., Zhu J. Z., Douglass, E. J., Uematsu, S., Akira, S., Wood, A. S., and Gowda, D. C. (<em>20</em>05) J. Biol. Chem. 280, 8606-8616) for the proinflammatory responses by macrophages. The data conclusively show that the production of TNF-alpha, interleukin (<em>IL</em>)-12, <em>IL</em>-6, and nitric oxide by macrophages stimulated with parasite GPIs is critically dependent on the NF-kappaB and JNK pathways. NF-kappaB1 is essential for <em>IL</em>-6 and <em>IL</em>-12 production but not for TNF-alpha and nitric oxide, whereas NF-kappaB/c-Rel appears to be important for all four proinflammatory mediators. JNK1 and JNK2 are functionally redundant for the expression of TNF-alpha, <em>IL</em>-6, and nitric oxide, whereas JNK2 but not JNK1 is essential for <em>IL</em>-12 production. The ERK signaling pathway is not involved in TNF-alpha and nitric oxide production, but, interestingly, negatively regulates the expression of <em>IL</em>-6 and <em>IL</em>-12. Furthermore, p38 is critical for the production of <em>IL</em>-6 and <em>IL</em>-12 but is only marginally required for the production of TNF-alpha and nitric oxide. Thus, our data define the differential requirement of the downstream signaling molecules for the production of key proinflammatory cytokines and nitric oxide by macrophages in response to P. falciparum GPI stimuli. The data have important implications for the development of therapeutics for malaria treatment.