Serum IL-1beta,sIL-2R,IL-6, IL-8 and TNF-alpha in schizophrenic patients,relation with symptomatology and responsiveness to risperidone treatment.

Activation of the inflammatory response system and varied levels of cytokines in acute schizophrenia have been suggested by recent studies. Psychopharmacologic agents can differentially effect cytokine production, which suggests that therapeutic function of neuroleptics may involve immunomodulation. The present study was carried out to examine: (i) serum concentrations of interleukin (IL)-1beta, soluble interleukin-2 receptor (sIL-2R), IL-6, IL-8 and tumour necrosis factor (TNF)-alpha in schizophrenic patients; (ii) their relation with psychopathological assessment; and (iii) the relation of the initial cytokine levels with responsiveness to risperidone therapy. Thirty-four drug-free schizophrenic patients with acute exacerbation and 23 age- and gender-matched healthy controls were recruited for this study. Psychopathological assessments at admission and throughout risperidone treatment for 60 days were recorded. Serum cytokine concentrations were determined with chemilumunescence assays. According to our results, serum IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha concentrations adjusted for age, gender, body mass index and smoking were no different in patients with schizophrenia and controls and among subtypes of schizophrenia. However, the initial TNF-alpha concentrations had a significant effect on Brief Psychiatric Rating Scale and Scale Assessment of Positive Symptoms scores. The initial cytokine concentrations of the patients responsive to risperidone were not significantly different from those of non-responsive patients. The present study demonstrates that plasma levels of IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha adjusted for confounding factors are not altered in drug-free schizophrenic patients at acute exacerbation. We suggest that, if cytokine production is altered in schizophrenia, these alterations may not be detectable in systemic circulation. According to our results, the therapeutic effect of risperidone is not related to basal levels of the aforementioned cytokines. However, serum TNF-alpha may contribute to symptomatology in schizophrenia     

Influence of acute alcohol intake and alcohol withdrawal on circulating levels of IL-6, IL-8, IL-10 and IL-12

Cytokine balance alterations are responsible for some of the systemic and hepatic manifestations of alcoholism. The present study was aimed to evaluate the influence of both acute alcohol abstinence (in alcoholics) and acute alcohol intake (in healthy subjects) on serum IL-6, IL-8, IL-10, and IL-12 levels. Serum cytokine concentrations were determined on admission and after a median of 6 days of ethanol abstinence in 29 patients with alcohol withdrawal syndrome. The same determinations were made in five healthy volunteers at baseline and after 36 h of a single 60 g-dose alcohol intake. Increased serum levels of IL-6, IL-10 and, to a lesser extent IL-8, declined in the few days after alcohol abstinence in patients with alcohol withdrawal syndrome. Serum IL-8 values increased after alcohol intake in healthy subjects. Rapid variation of serum cytokine levels along with alcohol intake or abstinence should be taken into account in cytokine studies in alcohol abusers.     

IL-6 enhances plasma IL-1ra,IL-10, and cortisol in humans

The purpose of the present study was to test the hypothesis that a transient increase in plasma IL-6 induces an anti-inflammatory environment in humans. Therefore, young healthy volunteers received a low dose of recombinant human (rh)IL-6 or saline for 3 h. Plasma IL-6 levels during rhIL-6 infusion were approximately 140 pg/ml, corresponding to the levels obtained during strenuous exercise. The infusion of rhIL-6 did not induce enhanced levels of the proinflammatory cytokine TNF-alpha but enhanced the plasma levels of the two anti-inflammatory cytokines IL-1 receptor agonist (IL-1ra) and IL-10 compared with saline infusion. In addition, C-reactive protein increased 3 h post-rhIL-6 infusion and was further elevated 16 h later compared with saline infusion. rhIL-6 induced increased levels of plasma cortisol and, consequently, an increase in circulating neutrophils and a decrease in the lymphocyte number without effects on plasma epinephrine, body temperature, mean arterial pressure, or heart rate. In conclusion, this study demonstrates that physiological concentrations of IL-6 induce an anti-inflammatory rather than an inflammatory response in humans and that IL-6, independently of TNF-alpha, enhances the levels not only of IL-1ra but also of IL-10. Furthermore, IL-6 induces an increase in cortisol and, consequently, in neutrocytosis and late lymphopenia to the same magnitude and with the same kinetics as during exercise, suggesting that muscle-derived IL-6 has a central role in exercise-induced leukocyte trafficking.     

Effect of hyperglycemia and hyperinsulinemia on the response of IL-6, TNF-alpha, and FFAs to low-dose endotoxemia in humans

Insulin therapy to maintain euglycemia increases survival in critically ill patients. To explore possible mechanisms of action, we investigated the effect of endotoxin on circulating cytokines, free fatty acids (FFA), and leukocytes during manipulated plasma glucose and insulin concentrations. Ten volunteers underwent three trials each, receiving an intravenous bolus of endotoxin (0.2 ng/kg) during normoglycemia (trial A, control), during a hyperglycemic clamp at 15 mM (trial B), and during a hyperinsulinemic euglycemic clamp (trial C). Endotoxin induced an increase in neutrophil count, a decrease in lymphocyte count, and an increase in serum levels of TNF-alpha, IL-6, and FFA. There was no difference in the TNF response between the three trials; the IL-6 levels were increased during the late phase of trials B and C compared with trial A. The endotoxin-induced elevation in FFA in trial A was suppressed during trials B and C. Clamping (trials B and C) caused a reduction in lymphocyte count that persisted after endotoxin injection. We conclude that low-dose endotoxemia triggers a subclinical inflammatory response and an elevation in FFA. The finding that high insulin serum concentrations induce a more prolonged increase in the anti-inflammatory cytokine IL-6 and suppress the levels of FFA suggests that insulin treatment of patients with sepsis may exert beneficial effects by inducing anti-inflammation and protection against FFA toxicity, and thereby inhibit FFA-induced insulin resistance.     

Shedding of Endogenous Interleukin-6 Receptor (IL-6R) Is Governed by A Disintegrin and Metalloproteinase (ADAM) Proteases while a Full-length IL-6R Isoform Localizes to Circulating Microvesicles

Generation of the soluble interleukin-6 receptor (sIL-6R) is a prerequisite for pathogenic IL-6 trans-signaling, which constitutes a distinct signaling pathway of the pleiotropic cytokine interleukin-6 (IL-6). Although in vitro experiments using ectopically overexpressed IL-6R and candidate proteases revealed major roles for the metalloproteinases ADAM10 and ADAM17 in IL-6R shedding, the identity of the protease(s) cleaving IL-6R in more physiological settings, or even in vivo, remains unknown. By taking advantage of specific pharmacological inhibitors and primary cells from ADAM-deficient mice we established that endogenous IL-6R of both human and murine origin is shed by ADAM17 in an induced manner, whereas constitutive release of endogenous IL-6R is largely mediated by ADAM10. Although circulating IL-6R levels are altered in various diseases, the origin of blood-borne IL-6R is still poorly understood. It has been shown previously that ADAM17 hypomorphic mice exhibit unaltered levels of serum sIL-6R. Here, by quantification of serum sIL-6R in protease-deficient mice as well as human patients we also excluded ADAM10, ADAM8, neutrophil elastase, cathepsin G, and proteinase 3 from contributing to circulating sIL-6R. Furthermore, we ruled out alternative splicing of the IL-6R mRNA as a potential source of circulating sIL-6R in the mouse. Instead, we found full-length IL-6R on circulating microvesicles, establishing microvesicle release as a novel mechanism for sIL-6R generation.     

Age-related limitations of interleukin-6 in predicting early mortality in acute ST-elevation myocardial infarction

Interleukin-6 (IL-6) is an inflammatory cytokine whose levels increase significantly during myocardial infarction (MI).It has been hypothesised that the concentrations of IL-6 at admission may be useful in prognosticating long-term outcomes. It is unclear, however, whether IL-6 could improve the prognosis of early mortality in MI.We have compared serum IL-6 levels and analysed the disease course in 158 patients with ST-elevation MI (STEMI) who either survived (n?=?148) or died (n?=?10) within 30 days following the admission. Patients were treated in a single university centre with primary percutaneous coronary intervention (PCI).The non-survivors (6.3%) displayed most of typical risk factors for poor outcome. In addition they had significantly higher concentrations of IL-6 at hospital admission (median values 8.5 vs. 2.0 pg/ml; p?=?0.038). However, they were also significantly older than the survivors (median values 72 vs. 57 years; p?=?0.0001). IL-6 levels are known to increase with age and we could confirm a significant correlation between patients’ calendar age and circulating IL-6 (p?=?0.009). Regression analysis revealed that IL-6 concentrations were significantly affected by patients’ age but they did not independently relate to patients’ outcome.Such results indicate that circulating IL-6 at admission may be of limited value in predicting early mortality in STEMI. It is important to recognize that, because of the small group of patients who died (N?=?10), the results must be interpreted with caution. Therefore, we stress that these results should be viewed as preliminary and further validated in a larger set of patients.     

Reversal of defective IL-6 production in lipopolysaccharide-tolerant mice by phorbol myristate acetate

The development of LPS tolerance has been suggested to be mediated by an inhibition of cytokine synthesis. Here we have studied serum IL-6 and TNF levels in mice after LPS administration. Repeated administration of LPS (35 micrograms daily for 4 days) to mice induced a refractoriness (tolerance) to subsequent administrations of LPS in terms of induction of circulating IL-6 and TNF. To investigate the mechanism by which LPS down-regulates its own induction of cytokine synthesis and the relationship between IL-6 and TNF production, we attempted to revert the inhibition of IL-6 and TNF production using agents like PMA or IFN-gamma, previously reported to activate macrophage production of cytokines. Pretreatment with PMA (4 micrograms, 10 min before LPS) partially restored IL-6 production in LPS-tolerant mice given 2 micrograms LPS. On the other hand, PMA did not restore TNF induction in LPS-tolerant mice, even when administered with high doses of LPS (up to 200 micrograms). A similar reversal of LPS resistance to IL-6, but not TNF, induction by PMA was observed in genetically LPS-resistant C3H/HeJ mice. IFN-gamma also restored, although to a lesser extent than PMA, IL-6 production. However, unlike PMA, IFN-gamma could also partially restore TNF production in LPS-tolerant mice, although only when LPS was administered at high doses. By contrast with PMA, IFN-gamma was clearly more active in restoring TNF synthesis than that of IL-6. Similar results were obtained in genetically LPS-unresponsive C3H/HeJ mice. These data suggest that different mechanisms are implicated in the inhibition of IL-6 and TNF synthesis in LPS-tolerant mice and that part of this inhibition can be overcome by PMA or IFN-gamma.     

Serum IL-1beta, IL-2, and IL-6 in insulin-dependent diabetic children

Insulin-dependent diabetes mellitus (IDDM) is a chronic disease characterized by T-cell-dependent autoimmune destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans, resulting in an absolute lack of insulin. T cells are activated in response to islet-dominant autoantigens, the result being the development of IDDM. Insulin is one of the islet autoantigens responsible for the activation of T-lymphocyte functions, inflammatory cytokine production, and development of IDDM. The aim of this study was to investigate serum concentrations of interleukin (IL)-1beta, IL-2, IL-6, and tumor necrosis factor (TNF)-alpha in children IDDM. The study population consisted of 27 children with IDDM and 25 healthy controls. Children with IDDM were divided into three subgroups: (1) previously diagnosed patients (long standing IDDM) (n : 15), (2) newly diagnosed patients with diabetic ketoacidosis (before treatment) (n : 12), and (3) newly diagnosed patients with diabetic ketoacidosis (after treatment for two weeks) (n : 12). In all stages of diabetes higher levels of IL-1beta and TNF-alpha and lower levels of IL-2 and IL-6 were detected. Our data about elevated serum IL-1beta, TNF-alpha and decreased IL-2, IL-6 levels in newly diagnosed IDDM patients in comparison with longer standing cases supports an activation of systemic inflammatory process during early phases of IDDM which may be indicative of an ongoing beta-cell destruction. Persistence of significant difference between the cases with IDDM monitored for a long time and controls in terms of IL-1beta, IL-2, IL-6, and TNF-alpha supports continuous activation during the late stages of diabetes.     

In vivo intracellular cytokine production by leukocytes during haemodialysis

Several chronic inflammatory changes undergone during chronic haemodialysis are associated with increased pro-inflammatory cytokine production. Although generation of anaphylatoxins has been incriminated in the untoward effects of haemodialysis, it is still debated whether anaphylatoxins stimulate monocyte secretion of TNF-alpha and IL-1. We demonstrate that peripheral mononuclear cells isolated from healthy controls and cultured with complement-activated autologous serum or recombinant C5a induced high levels of IL-1, IL-1ra, IL-8 and MCP-1, low levels of TNFalpha and sTNFRII but no IL-10 and MIP-1alpha. Cytokine production by leukocytes was investigated by FACS analysis in six patients dialysed consecutively with three equivalent low permeability membranes known to activate the complement to different degrees: polysulfone (F6HPS), cellulose acetate (CA) and cuprophane (CP). Percentage of leukocytes expressing IL-1, IL-1ra, TNF-alpha and IL-8 is increased in patients dialysed with CP. Moreover, we show for the first time that haemodialysis is associated with the production of cytokines by circulating neutrophils. Predialysis plasma levels of MCP-1 and TNFRII did not increase during the dialysis session at the time when anaphylatoxin generation was highest. Dialysis with membranes that activate the complement to a high extent induce activation of leukocytes which may explain chronic complications associated with dialysing with CP.     

IL-1 stimulates IL-6 production in endothelial cells

Leukocytes and vascular cells interact closely in inflammation and immunity and lymphokines are important mediators of this interaction. The present study was designed to define the possible role of IL-6 as a communication signal between vascular and immunocompetent cells. IL-6 was measured as hybridoma growth factor (HGF) on the 7TD1 cell line in the supernatants of human endothelial cells (HEC). HEC released appreciable levels of HGF activity in the absence of deliberate stimulation. In vitro exposure to recombinant IL-1 beta markedly increased (usually 10 to 15-fold) HGF production by HEC. Optimal stimulation was observed with 0.1 to 50 U/ml for 4 to 20 h of incubation. Human and murine rIL-1 alpha stimulated HGF production in HEC. Anti-IL-6 antibodies inhibited the HGF activity of the HEC supernatants, thus confirming, together with the cytokine specificity of the assay, the nature of HEC-produced cytokine. IL-1-treated HEC expressed high levels of IL-6 mRNA as detected by Northern blot analysis. Inasmuch as IL-1 elicits a complex series of changes in HEC, it was important to assess whether IL-6, produced after exposure to IL-1, modified HEC function. Natural or rIL-6 did not affect the functional status of HEC as assessed by proliferative capacity, production of procoagulant activity and prostacyclin, ability to induce adhesion of polymorphonuclear leukocytes. The capacity to produce IL-6 may represent an important mechanism by which endothelial cells participate in inflammatory and immune reactions.     

White adipose tissue production and release of IL-6 and TNF-alpha do not parallel circulating and cerebrospinal fluid concentrations in pregnant rats.

IL-6 and TNF-alpha are synthesized in white adipose tissue both by adipocytes and by the stroma-vascular fraction. They both are known to interfere with insulin signaling, reducing insulin sensitivity and lipid deposition. At a central level, IL-6 enhances sympathetic nervous system activity, thus enhancing lipolysis and reducing fat mass. During late pregnancy, white adipose tissue (WAT) mass increases and insulin sensitivity decreases. To assess the involvement of both adipokines in such processes, we analyzed the tissue content and release of both adipokines in parametrial and subcutaneous WAT depots and their circulating and cerebrospinal fluid concentrations in nonpregnant rats and in pregnant rats by days 8, 15, and 19 of pregnancy. The tissue content of both adipokines was enhanced 5-6 times by day 8 until the end of pregnancy in parametrial WAT, whereas the increase took place by day 15-19 in subcutaneous WAT. No increase in tissue release was detected, suggesting a local action. However, circulating IL-6 concentration was enhanced by day 8 until the end of pregnancy, suggesting sources other than WAT. IL-6 concentration in cerebrospinal fluid paralleled the increases in serum by days 8 and 15, suggesting a systemic origin. However, it returned to basal levels by day 19, suggesting a central control for IL-6 entrance. TNF-alpha was not detected in either serum or cerebrospinal fluid. These results led us to conclude that across pregnancy adipokines control WAT depots in a time- and depot-dependent manner. They do so directly, by local production, but the enhanced concentrations of both circulating and CSF IL-6 suggest an indirect action mediated by the nervous system.     

IL-6-induced skeletal muscle atrophy.

Chronic, low-level elevation of circulating interleukin (IL)-6 is observed in disease states as well as in many outwardly healthy elderly individuals. Increased plasma IL-6 is also observed after intense, prolonged exercise. In the context of skeletal muscle, IL-6 has variously been reported to regulate carbohydrate and lipid metabolism, increase satellite cell proliferation, or cause muscle wasting. In the present study, we used a rodent local infusion model to deliver modest levels of IL-6, comparable to that present after exercise or with chronic low-level inflammation in the elderly, directly into a single target muscle in vivo. The aim of this study was to examine the direct effects of IL-6 on skeletal muscle in the absence of systemic changes in this cytokine. Data included cellular and molecular markers of cytokine and growth factor signaling (phosphorylation and mRNA content) as well as measurements to detect muscle atrophy. IL-6 infusion resulted in muscle atrophy characterized by a preferential loss of myofibrillar protein (-17%). IL-6 induced a decrease in the phosphorylation of ribosomal S6 kinase (-60%) and STAT5 (-33%), whereas that of STAT3 was increased approximately twofold. The changes seen in the IL-6-infused muscles suggest alterations in the balance of growth factor-related signaling in favor of a more catabolic profile. This suggests that downregulation of growth factor-mediated intracellular signaling may be a mechanism contributing to the development of muscle atrophy induced by elevated IL-6.     

IL-6 Trans-Signaling via the Soluble IL-6 Receptor: Importance for the Pro-Inflammatory Activities of IL-6

Interleukin-6 (IL-6) is a cytokine with many activities. It has functions in the regulation of the immune system and the nervous system. Furthermore, IL-6 is involved in liver regeneration and in the metabolic control of the body. On target cells, IL-6 binds to an 80 kDa IL-6 receptor (IL-6R). The complex of IL-6 and IL-6R associates with a second protein, gp130, which thereupon dimerizes and initiates intracellular signaling. Whereas gp130 is expressed on all cells, IL-6R is only present on few cells in the body including hepatocytes and some leukocytes. Cells, which do not express IL-6R cannot respond to the cytokine, since gp130 alone has no measurable affinity for IL-6. Interestingly, a soluble form of IL-6R (sIL-6R) comprising the extracellular portion of the receptor can bind IL-6 with a similar affinity as the membrane bound IL-6R. The complex of IL-6 and sIL-6R can bind to gp130 on cells, which do not express the IL-6R, and which are unresponsive to IL-6. This process has been called trans-signaling. Here I will review published evidence that IL-6 trans-signaling is pro-inflammatory whereas classic IL-6 signaling via the membrane bound IL-6R is needed for regenerative or anti-inflammatory activities of the cytokine. Furthermore, the detailed knowledge of IL-6 biology has important consequences for therapeutic strategies aimed at the blockade of the cytokine IL-6.     

IL-6 -174G/C polymorphism and IL-6 serum levels in patients with liver cirrhosis and hepatocellular carcinoma

Recently, a link between high levels of circulating IL-6 and hepatocellular carcinoma (HCC) has been proposed. In addition, single nucleotide polymorphisms (SNPs) in the promoter region of the IL-6 gene have been reported to be related to several inflammatory-related conditions, including cancer. The purpose of this article is: (1) to evaluate the frequencies of SNPs in the IL-6 promoter region at position -174 and IL-6 serum levels in a group of patients with HCC and underlying liver cirrhosis (LC), and compare them with a group of LC patients without HCC; (2) to determine whether a possible correlation exists between the allelic variations, IL-6 serum levels, and the risk of developing HCC. The study included 105 HCC and 95 LC patients. Genomic DNA was isolated using commercially available kits. DNA samples were typed for relevant SNPs of the IL-6 promoter region (-174?G>C, G allele being associated with higher levels of the cytokine). The Restriction Fragment Length Polymorphism (RFLP-PCR) method was used to type the SNPs. IL-6 serum levels were determined using an ultrasensitive commercially available ELISA kit. IL-6 serum levels were higher in G/G compared to C/C genotypes only in HCC (z=2; p=0.04) and G/G versus G/C (z=1.8; p<0.03). IL-6 serum levels in G carriers (G/G+G/C) were higher in HCC 4.8 (0.2-17.5) versus LC patients 2.2 (0.07-11.5) (z=2.8; p=0.004). There was no difference for genotype C/C. IL-6 serum levels in HCC correlated with G carriers (G/G+G/C) (ρ=0.25, p=0.05). A positive correlation was also found between sIL-6 levels and some parameters of liver function both in LC and in HCC patients.     

IL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study

Interleukin-6 (IL-6) and C-reactive protein (CRP) levels increase with age and likely play a role in adverse health outcomes in older adults. The relationship between IL-6 gene tag single nucleotide polymorphisms (SNPs) and circulating IL-6 and CRP levels, cardiovascular disease (CVD) outcomes, and mortality in Caucasian (CA) and African American (AA) participants of the Cardiovascular Health Study (CHS) was evaluated using ANCOVA and Cox proportional hazards models. The minor allele of the promoter SNP 1510 and intronic SNP 3572 associates with significantly higher serum IL-6 and CRP levels in CA but not AA. The CRP association persisted after CA and AA populations were combined and after accounting for multiple comparisons. These associations did not carry through to cardiovascular disease outcomes. Decreased risk of stroke was identified in CA, with the minor allele of SNP 1111 (HRR 0.71, 95% CI 0.52, 0.95), P = 0.02, and increased risk of CVD and all-cause mortality (HRR 1.31, 95% CI 1.05–1.64) in AAs heterozygote for SNP 2989. While genetic variation in the IL-6 gene was associated with circulating IL-6 and especially with CRP concentrations in this study, there is little evidence for association between common IL-6 gene variation and adverse health outcomes in this population of older adults.     

Plasma concentration of interleukin 6 (IL-6), and its relationship with circulating concentration of dehydroepiandrosterone sulfate (DHEA-S) in patients with chronic idiopathic urticaria

Decline in circulating DHEA-S concentration may be a phenomenon accompanying chronic idiopathic urticaria (CIU). IL-6 is a multifunctional proinflammatory cytokine which exerts a wide range of biological effects. A functional link between DHEA-S and IL-6 has been described. Therefore, the present study was performed to evaluate circulating concentration of IL-6 in patients with CIU and to study its relationship with DHEA-S and C-reactive protein (CRP) concentration. IL-6 plasma concentration was determined in 18 female non-atopic patients with CIU who had negative response to autologous serum skin test and 20 non-atopic healthy controls. Plasma concentration of IL-6 was statistically higher in CIU patients than in the control group, although all the values were found within the range of the normal subjects. CIU patients showed significantly lower DHEA-S concentration in serum than the controls. CRP concentration remained within the normal range and did not differ between the two groups. We did not find a significant correlation between concentration of IL-6 and DHEA-S, or CRP. It seems that the processes associated with CIU may be accompanied by slightly elevated plasma concentration of IL-6 and substantially decreased serum concentration of DHEA-S as compared with the healthy subjects. However, no association between IL-6 and DHEA-S concentration in the peripheral circulation of CIU patients was proved, suggesting that both phenomena may not be related to each other.