Brain IL-6- and PG-dependent actions of IL-1β and lipopolysaccharide in avian fever

There is no persuasive evidence of a correlation between proinflammatory cytokines and avian fever. In this study, for the first time, we use avian cytokines to investigate a role for proinflammatory cytokines in the central component of avian fever. IL-1β and IL-6 injected intracerebroventricularly into Pekin ducks (n = 8) initiated robust fevers of equal magnitude and duration, although there was a significant difference in the latency to a febrile response. In addition, the IL-1β-induced fever could be abolished with an intracerebroventricular injection of antibodies to avian IL-6 or an oral administration of a PG synthesis inhibitor. Our findings indicate the following sequence of events within the central component of the avian febrile mechanism: IL-1β gives rise to bioactive IL-6, which stimulates an accelerated synthesis of PGs, and these PGs then adjust the sensitivity of warm-sensitive neurons in the avian brain stem to mediate fever. Yet PGE? was not upregulated in the cerebrospinal fluid of ducks made febrile with LPS. We conclude that IL-1β and IL-6 may well mediate fever by instigating an accelerated synthesis of brain-derived PG, of a class other than PGE?, or that IL-6 serves as one of the terminal mediators of the avian febrile response.     

A new regulation of IL-6 production in adult cardiomyocytes by β-adrenergic and IL-1β receptors and induction of cellular hypertrophy by IL-6 trans-signalling

The sympathetic nervous system and pro-inflammatory cytokines play key roles in numerous cardiovascular disorders. Chronic β-adrenergic receptor (β-AR) stimulation in myocardium induces expression of pro-inflammatory cytokines, such as interleukin-1 (IL-1) and interleukin-6 (IL-6), which contribute to cardiac hypertrophy and failure. To evaluate the relationship between β-AR stimulation and pro-inflammatory cytokines, we studied the effects of the β-AR agonist isoprenaline (ISO) on IL-1-induced IL-6 production in adult rat ventricular myocytes (ARVMs). We report that ISO and IL-1 synergistically enhanced IL-6 gene expression and secretion. The synergistic effect of ISO was mimicked by cAMP elevating agents and involved the G_s protein/cAMP/PKA signalling pathway, but not the exchange factor EPAC. To evaluate the contribution of IL-6 to cellular hypertrophy, we examined the signalling pathways stimulated by the membrane-bound IL-6 receptor (IL-6R), and the IL-6 soluble receptor (sIL-6R) involved in the mechanism named IL-6 trans-signalling. The IL-6/sIL-6R complex promoted a rapid and persistent phosphorylation of STAT3^Tyr705 in ARVMs. Moreover, IL-6 trans-signalling increased protein synthesis, c-fos gene expression and B-type natriuretic peptide secretion, three markers of cardiac hypertrophy. IL-6 trans-signalling also increased cell size. In contrast, IL-6 alone had no significant effect on either cell size or STAT3 phosphorylation although it induced phosphorylation of ERK1/2, AKT and S6K, demonstrating the presence of a functional IL-6R in ARVMs. Taken together, these results demonstrate that β-AR stimulation synergises with IL-1 for IL-6 secretion in adult ventricular myocytes and indicate that IL-6 induces cardiac hypertrophy only via IL-6 trans-signalling. The IL-6 soluble receptor may thus serve as a switch for IL-6 to activate STAT3 phosphorylation and hypertrophy.     

IL-1β, IL-6, and RANTES as Biomarkers of Chikungunya Severity

Background

Little is known about the immunopathogenesis of Chikungunya virus. Circulating levels of immune mediators and growth factors were analyzed from patients infected during the first Singaporean Chikungunya fever outbreak in early 2008 to establish biomarkers associated with infection and/or disease severity.

Methods and Findings

Adult patients with laboratory-confirmed Chikungunya fever infection, who were referred to the Communicable Disease Centre/Tan Tock Seng Hospital during the period from January to February 2008, were included in this retrospective study. Plasma fractions were analyzed using a multiplex-microbead immunoassay. Among the patients, the most common clinical features were fever (100%), arthralgia (90%), rash (50%) and conjunctivitis (40%). Profiles of 30 cytokines, chemokines, and growth factors were able to discriminate the clinical forms of Chikungunya from healthy controls, with patients classified as non-severe and severe disease. Levels of 8 plasma cytokines and 4 growth factors were significantly elevated. Statistical analysis showed that an increase in IL-1β, IL-6 and a decrease in RANTES were associated with disease severity.

Conclusions

This is the first comprehensive report on the production of cytokines, chemokines, and growth factors during acute Chikungunya virus infection. Using these biomarkers, we were able to distinguish between mild disease and more severe forms of Chikungunya fever, thus enabling the identification of patients with poor prognosis and monitoring of the disease.     

Carbon nanotubes provoke inflammation by inducing the pro-inflammatory genes IL-1β and IL-6

Carbon nanotubes (CNTs) are largely produced and widely used because of their novel features, and the annual yield is expected to increase dramatically in the near future. Meanwhile, adverse health influences from exposure to CNTs are widely concerned, partially due to their asbestoid characteristics. In the current study, to assess the inflammatory responses and related mechanisms, we established a mouse model of chronic exposure to CNTs using intraperitoneal injection of single-walled carbon nanotubes (SWNTs) and multi-walled carbon nanotubes (MWNTs). Our results demonstrated the fibre-like pathogenic behaviors of CNTs, reflected by increased total protein content in the lavageate from peritoneal cavities and increased serum levels of inflammatory cytokines, IL-1β and IL-6. The pro-inflammatory effects of CNTs were further validated with exposure to in vitro cultured monocyte-macrophage cells, J774A.1, as SWNTs and MWNTs significantly increased the expression levels of pro-inflammatory genes IL-1β and IL-6. Collectively, our data demonstrate that SWNTs and MWNTs provoke considerable inflammation presumably due to their fibre-like shape, and further confirm the length- and size-related structure-activity relationship for CNTs in stimulating inflammatory responses.     

Regulation of glycosyltransferases and Lewis antigens expression by IL-1β and IL-6 in human gastric cancer cells

Inflammation of stomach mucosa has been postulated as initiator of gastric carcinogenesis and the presence of pro-inflammatory cytokines can regulate specific genes involved in this process. The cellular expression pattern of glycosyltransferases and Lewis antigens detected in the normal mucosa changed during the neoplassic transformation. The aim of this work was to determine the regulation of specific fucosyltransferases and sialyltransferases by IL-1β and IL-6 pro-inflammatory cytokines in MKN45 gastric cancer cells. IL-1β induced significant increases in the mRNA levels of FUT1, FUT2 and FUT4, and decreases of FUT3 and FUT5. In IL-6 treatments, enhanced FUT1 and lower FUT3 and FUT5 mRNA expression were detected. No substantial changes were observed in the levels of ST3GalIII and ST3GalIV. The activation of FUT1, FUT2 and FUT4 by IL-1β is through the NF-κB pathway and the down-regulation of FUT3 and FUT5 by IL-6 is through the gp130/STAT-3 pathway, since they are inhibited specifically by panepoxydone and AG490, respectively. The levels of Lewis antigens after IL-1β or IL-6 stimulation decreased for sialyl-Lewis x, and no significant differences were found in the rest of the Lewis antigens analyzed, as it was also observed in subcutaneous mice tumors from MKN45 cells treated with IL-1β or IL-6. In addition, in 61 human intestinal-type gastric tumors, sialyl-Lewis x was highly detected in samples from patients that developed metastasis. These results indicate that the expression of the fucosyltransferases involved in the synthesis of Lewis antigens in gastric cancer cells can be specifically modulated by IL-1β and IL-6 inflammatory cytokines.     

IL-6 and IL-10 Anti-Inflammatory Activity Links Exercise to Hypothalamic Insulin and Leptin Sensitivity through IKKβ and ER Stress Inhibition

Overnutrition caused by overeating is associated with insulin and leptin resistance through IKKβ activation and endoplasmic reticulum (ER) stress in the hypothalamus. Here we show that physical exercise suppresses hyperphagia and associated hypothalamic IKKβ/NF-κB activation by a mechanism dependent upon the pro-inflammatory cytokine interleukin (IL)-6. The disruption of hypothalamic-specific IL-6 action blocked the beneficial effects of exercise on the re-balance of food intake and insulin and leptin resistance. This molecular mechanism, mediated by physical activity, involves the anti-inflammatory protein IL-10, a core inhibitor of IKKβ/NF-κB signaling and ER stress. We report that exercise and recombinant IL-6 requires IL-10 expression to suppress hyperphagia-related obesity. Moreover, in contrast to control mice, exercise failed to reverse the pharmacological activation of IKKβ and ER stress in C3H/HeJ mice deficient in hypothalamic IL-6 and IL-10 signaling. Hence, inflammatory signaling in the hypothalamus links beneficial physiological effects of exercise to the central action of insulin and leptin.     

Serum TNF-α, sTNFR1, IL-6, IL-8 and IL-10 levels in Weil's syndrome

Studies on cytokine levels in Weil's syndrome are lacking. In this study, TNF-α, sTNFR1, IL-6, IL-8 and IL-10 levels were measured in 44 serum samples of patients diagnosed with Leptospira interrogans serovar icterohaemorrhagiae infection. TNF-α levels linked with pulmonary hemorrhagic implications, while elevated sTNFR1 and IL-10 levels linked with fatal cases. IL-6 and IL-8 did not seem to affect the outcome of the disease. Immune response pattern in Weil's syndrome bears resemblance to other patterns described for hemorrhagic fevers. IL-10/TNF-α ratio is proposed as a marker for prognosis.     

Regulation of IL-6 and IL-8 production by reciprocal cell-to-cell interactions between tumor cells and stromal fibroblasts through IL-1α in ameloblastoma

Ameloblastoma is an odontogenic benign tumor that occurs in the jawbone, which invades bone and reoccurs locally. This tumor is treated by wide surgical excision and causes various problems, including changes in facial countenance and mastication disorders. Ameloblastomas have abundant tumor stroma, including fibroblasts and immune cells. Although cell-to-cell interactions are considered to be involved in the pathogenesis of many diseases, intercellular communications in ameloblastoma have not been fully investigated. In this study, we examined interactions between tumor cells and stromal fibroblasts via soluble factors in ameloblastoma.     

Association of IL-6, TNF-α and IL-10 gene polymorphisms with type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a metabolic pro-inflammatory disorder characterized by chronic hyperglycemia and increased levels of circulating cytokines suggesting a causal role of inflammation in its etiology. Polymorphism of cytokine genes including interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and interleukin-10 (IL-10) were studied in T2DM patients as well as in normal healthy controls. Genomic DNA was isolated from both T2DM patients and controls followed by quantification and genotyping by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) using suitable primers. The genotypic, allelic and carriage rate frequency distribution in patients and controls were analyzed by SPSS (version 15.0). Odd ratios with 95 % confidence interval was determined to describe the strength of association by logistic regression model. Double and triple combinations of genotypes were analyzed by χ² test. Gene–gene interaction and linkage disequilibrium tests were performed using SHEsis software. Individually, IL-6, TNF-α and IL-10 did not show any association. In double combination, IL-6 ?597 GA and TNF-α ?308 GG genotypes increased the risk up to 21 times and in triple combination IL-6 ?597 AA, TNF-α ?308 GG and IL-10 ?592 CA increased the risk of T2DM up to 314 times. In gene–gene interaction allele ‘A’ of all studied polymorphisms increased the risk of T2DM up to 1.41 times. Our results suggest that individuals having a haplotype combination of AA, GG and CA for IL-6, TNF-α and IL-10 gene polymorphisms will have higher susceptibility and be at greater risk of developing T2DM.     

IL-1β Suppresses Innate IL-25 and IL-33 Production and Maintains Helminth Chronicity

Approximately 2 billion people currently suffer from intestinal helminth infections, which are typically chronic in nature and result in growth retardation, vitamin A deficiency, anemia and poor cognitive function. Such chronicity results from co-evolution between helminths and their mammalian hosts; however, the molecular mechanisms by which these organisms avert immune rejection are not clear. We have found that the natural murine helminth, Heligmosomoides polygyrus bakeri (Hp) elicits the secretion of IL-1β in vivo and in vitro and that this cytokine is critical for shaping a mucosal environment suited to helminth chronicity. Indeed in mice deficient for IL-1β (IL-1β^−/−), or treated with the soluble IL-1βR antagonist, Anakinra, helminth infection results in enhanced type 2 immunity and accelerated parasite expulsion. IL-1β acts to decrease production of IL-25 and IL-33 at early time points following infection and parasite rejection was determined to require IL-25. Taken together, these data indicate that Hp promotes the release of host-derived IL-1β that suppresses the release of innate cytokines, resulting in suboptimal type 2 immunity and allowing pathogen chronicity.     

Membrane-bound/soluble IL-2 receptor (IL-2R) and levels of IL-1α, IL-2, and IL-6 in the serum and in the PBMC culture supernatants from 17 patients with hematological malignancies

The present study investigated the peripheral blood mononuclear cells (PBMC) blastic responses to PHA, PHA plus recombinant IL-2 (rIL-2) and rIL-2 alone; the expression of membrane-bound IL-2R on PHA-stimulated PBMC; and the levels of IL-1α, IL-2, IL-6, and sIL-2R in serum and in culture supernatants from PHA-stimulated PBMC in 17 patients with hematological malignancies (mean age 58.5 yr, range 22–82): 6 with non-Hodgkin’s lymphoma (NHL), 4 with Hodgkin’s lymphoma (HL), 5 with Hairy cell leukemia, 1 with chronic myelogenous leukemia, and 1 with chronic lymphocytic leukemia. The patients with HL and NHL with active disease (AD) were separated from those in clinical remission. The patients with AD were studied at diagnosis (obviously before therapy) and the patients in clinical remission were out of therapy since at least 6 mo. The lymphocyte blastogenic response to PHA was significantly lower in patients with HL and NHL with AD than in the control group. The response to rIL-2 alone was in the same range in the control group and in HL and NHL AD patients. By adding rIL-2 to PHA there was an increase of the blastogenic response of the same patients. The percentage of CD25 expressed on PHA-stimulated lymphocytes from patients with HL and NHL AD and from normal subjects is in the same range. Serum levels of IL-2, IL-6, and sIL-2R were significantly higher in HL and NHL AD patients than in controls as well as in all other hematological malignancies. Supernatants derived from PHA-stimulated PBMC were assessed for the presence of cytokines and sIL-2R by ELISA. The levels of IL-2, IL-6, and sIL-2R were significantly lower in HL and NHL AD patients than in controls as well as in all other hematological malignancies.     

Evaluation of TNF-α, IL-10 and IL-6 Cytokine Production and Their Correlation with Genotype Variants amongst Tuberculosis Patients and Their Household Contacts

Background

Household contacts of diagnostically established tuberculosis (TB) patients are highly susceptible to disease development. It is surmised that cytokines perhaps play a synergistic and a prognostic role in the activation of the otherwise latent infection in these house hold contacts. Evaluation of the cytokines and any of their inherent polymorphisms might provide a useful diagnostic tool in evaluating the immune regulation and the progression of the disease. The cytokines thus released in a paracrine manner in serum may also provide an indirect measure of the cytokine function.

Objective

The present study was aimed to evaluate the levels of TNF-α, IL-10 & IL-6 cytokines and their correlation with genotype variants amongst tuberculosis patients and their household contacts.

Methods

The cytokine levels were estimated in serum by enzyme-linked immunosorbent assay (ELISA) and their polymorphisms were studied by amplification refractory mutation system polymerase chain reaction (ARMs PCR) in active pulmonary tuberculosis patients (APTB = 150), household contacts (HHC = 190), and healthy controls (HC = 150).

Results

The median values of TNF-α cytokine were significantly high among APTB and HHC compared to HCs (P< 0.0001 and 0.0001). IL-6 levels also were elevated among APTB compared to HHC and HC, and a significant difference was observed between APTB and HHC at P<0.0001; APTB & HC at P< 0.04; HHC & HC at P< 0.01. The IL-10 levels were low in APTB compared to HHC and HCs and no significant difference was observed. TNF-α/IL-10 ratio was significant and indicated Th1 predominance in APTB and HHC. IL-6/IL-10 showed pronounced Th1 expression in APTB and Th2 in HHC and HC. The ROC analysis indicated that both IL-10 and IL-6 can be used to decide the risk of exposed individual to a disease. The results of multivariate analysis indicate that IL-10 (-1082) GA genotype was significantly associated with p<0.028 in APTB. No significant association was observed between genotypes, other serum cytokine levels and clinical characteristics between APTB, HHC and HCs.

Conclusion

Large sample size with follow-up at different time points may further illuminate the role of IL-10 and IL-6 cytokines as a prognostic marker in house hold contacts.     

IL-1，IL-6，IL-8 与胃癌的关系

胃癌是常见的恶性肿瘤之一,在我国其发病率居各类肿瘤前列,导致的死亡人数占所有肿瘤的四分之一,而且每年有近40万新增的胃癌病人,但是其早期诊断率低于20%,胃癌已经成为危害人民健康的最严重的疾病之一。白细胞介素(interleukin,IL)作为在白细胞或免疫细胞间相互作用的淋巴因子,不仅在介导T、B细胞活化、增殖与分化以及炎症反应中起着重要作用,近年来,越来越多的学者发现其与肿瘤的发生及发展也有着密不可分的联系。目前为止,已经发现了29种白细胞介素,分别被命名为IL-1~IL-29,它们各自承担着相应的使命。国内外大量实验及文献表明,IL-1,IL-6,IL-8和胃癌有着密切的关系,这对于胃癌的早期诊断及治疗提出了新的思路,进而提高胃癌的早期诊断率,改善胃癌的治疗状况。本文对IL-1,IL-6,IL-8的来源、分子结构及受体方面进行简要概述,同时阐述了其生物学特性及与胃癌的关系。     

Atherogenic effects of TNF-α and IL-6 via up-regulation of scavenger receptors

Patients with chronic inflammatory disorders such as rheumatoid arthritis (RA) have a high risk of developing cardiovascular disease. We evaluated the effects of TNF-α and IL-6 on foam cell formation, a pivotal process in atherogenesis. Accumulation of intracellular oxidized LDL (oxLDL) was induced when THP-1/macrophages were stimulated with TNF-α or IL-6. TNF-α induced the expressions of scavenger receptors SR-A and LOX-1, and IL-6 induced SR-A expression. Inhibition of the NF-κB signaling markedly decreased TNF-α-induced foam cell formation and SR-A expression. Serum from RA patients, but not healthy subjects, induced foam cell formation, which was partially reversed by either IL-6 or TNF-α blockade in conjunction with inhibiting the induction of scavenger receptors. The present study clearly showed that in patients with chronic inflammation mediated by TNF-α and IL-6, these cytokines are directly implicated in atherosclerotic plaque formation.     

Choline Uptake and Metabolism Modulate Macrophage IL-1β and IL-18 Production

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Serum IL-10 and IL-6 levels at diagnosis as independent predictors of outcome in non-Hodgkin’s lymphoma

Interleukin 10 (IL-10) and interleukin 6 (IL-6) are widely investigated in solid tumors as being important prognostic factors. IL-10 and IL-6 serum levels were measured by enzyme-linked immunosorbent assay from sera taken from 40 non-Hodgkin's lymphoma (NHL) patients before and after treatment and from 20 healthy controls. The patients had been observed for at least 18 months or until death. IL-10 and IL-6 were significantly higher in NHL patients compared to controls. IL-6 was correlated with IL-10 (r = 0.451) and with B symptoms (weight loss > 10% during the last 6 months, unexplained fever and night sweats) (r = 0.447). IL-10 and IL-6 were significantly higher in non survival compared to survival group. High pretreatment IL-10 and IL-6 was associated with poor overall survival. These results show that IL-10 and IL-6 levels are elevated in NHL patients and seem to suggest that simultaneous elevation of IL-10 and IL-6 is a powerful negative prognostic parameter in NHL.