Muscle-derived interleukin-6: possible biological effects

Interleukin-6 (IL-6) is produced locally in working skeletal muscle and can account for the increase in plasma IL-6 during exercise. The production of IL-6 during exercise is related to the intensity and duration of the exercise, and low muscle glycogen content stimulates the production. Muscle-derived IL-6 is released into the circulation during exercise in high amounts and is likely to work in a hormone-like fashion, exerting an effect on the liver and adipose tissue, thereby contributing to the maintenance of glucose homeostasis during exercise and mediating exercise-induced lipolysis. Muscle-derived IL-6 may also work to inhibit the effects of pro-inflammatory cytokines such as tumour necrosis factor α. The latter cytokine is produced by adipose tissue and inflammatory cells and appears to play a pathogenetic role in insulin resistance and atherogenesis.     

白细胞介素-21的免疫调节机制

白细胞介素-21（IL-21）是由激活的CD4^＋T细胞产生的细胞因子.IL-21受体（IL-21R）与IL-2R、IL-4R、IL-7R、ID9R、IL-15R等受体享有共同的受体γ链,广泛表达于免疫细胞上,介导各种免疫效应.IL-21能够增强免疫效应细胞增殖、抗原诱导的激活、克隆扩增,IFN-γ产生,以及NK细胞和T细胞的细胞毒效应.IL-21在被发现之初是作为抗肿瘤因子,最近发现IL-21与自身免疫和炎症性疾病具有相关性.     

B-cell-derived lymphokines: regulatory effects on the immune system

While both regulatory and effector functions within the T cell lineage have been extensively studied, B lymphocytes have been considered merely a source of humoral antibodies until recently. With the exception of antibody feedback, only a limited number of investigations have been designed to explore the possibility that B cells may exert regulatory activity. The purpose of this review is to analyze how B cells can modulate themselves by generating signals (lymphokines), which under certain circumstances may initiate a chain of regulatory events. Only factors exclusively produced by B cells are considered. While, for the most part, this review is dedicated to recent studies on nonimmunoglobulin B cell factors, the role played by Ig molecules as immunoregulatory linker molecules, independently of their antigenic specificity, will be briefly examined. Furthermore, some basic questions regarding the biological significance of these regulatory mechanisms will be raised.     

6-aryl-4-oxohexanoic acids: synthesis, effects on eicosanoid biosynthesis, and anti-inflammatory in vivo-activities

The synthesis of a series of 6-aryl-4-oxohexanoic acids is described: This involves condensation of an appropriate aldehyde (Ia-f) and levulenic acid using catalytic amounts of piperidine and acetic acid in toluene to afford the 6-aryl-4-oxohex-5-enoic acids (IIa-f). The arylidene derivatives (IIa-d) were reduced by hydrogen at room temperature using palladium (10 %/carbon) as catalyst to produce 6-aryl-4-oxohexanoic acids (IIIa-d) as target compounds. In certain instances, the lactone derivative (IVd) was obtained as a low-melting by-product. These compounds were tested in two models used for evaluating the activity of non-steroidal anti-inflammatory drugs (NSAIDs). The first test is the effect of the synthesized compounds on arachidonic acid metabolism in vitro using human whole blood assay. The second is the in vivo carrageenan induced rat paw edema test. Compound IIe showed higher in vivo-activity compared to fenbufen at the same dose level (50mg/kg).     

Immune complex-induced interleukin-6, interleukin-10 and prostaglandin secretion by human monocytes: a network of pro- and anti-inflammatory cytokines dependent on the antigen: antibody ratio

We have used two experimental models of immune complexes to study the secretion of interleukin (IL)-10, IL-6 and their connection with the immune complex-induced synthesis of prostaglandin (PG) E2 by human monocytes in vitro. Immune complexes formed of tetanus toxoid and polyclonal anti-tetanus toxoid antiserum as well as heat-aggregated human serum immunoglobulins induced the release of IL-6 and IL-10 in a dose- and antigen: antibody ratio-dependent manner. Antigen-antibody complexes formed near equivalence were most effective in induction of a cytokine response. PGE2 could augment the immune complex-induced IL-6 and IL-10 secretion, but alone, did not induce cytokine secretion. IL-10 was capable of down-regulating the release of IL-6 and PGE2. Additionally, we demonstrated that endogenously synthesized IL-10 limited the immune complex-induced secretion of proinflammatory cytokines tumor necrosis factor-α and IL-1β. All three regulatory factors examined here share anti-inflammatory properties and are closely associated with the T helper type 2 (Th2) immune response. We conclude that immune complexes, besides their well-known ability no cause acute and chronic inflammation, can mediate immunosuppressive effects and influence the balance of Th1/Th2 responses.     

Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells

Specific immune suppression and induction of tolerance are essential processes in the regulation and circumvention of immune defence. The balance between allergen-specific type 1 regulatory (Tr1) cells and T helper (Th) 2 cells appears to be decisive in the development of allergy. Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals. In contrast, there is a high frequency of allergen-specific interleukin-4 (IL-4)-secreting T cells in allergic individuals. Allergen-specific immunotherapy can induce specific Tr1 cells that abolish allergen-induced proliferation of Th1 and Th2 cells, as well as their cytokine production. Tr1 cells utilize multiple suppressor mechanisms, such as IL-10 and transforming growth factor-beta (TGF-beta) as secreted cytokines and various surface molecules, such as cytotoxic T-lymphocyte antigen 4 and programmed death-1. IL-10 only inhibits T cells stimulated by low numbers of triggered T-cell receptors, which depend on CD28 costimulation. IL-10 inhibits CD28 tyrosine phosphorylation, preventing the binding of phosphatidylinositol 3-kinase p85 and consequently inhibiting the CD28 signalling pathway. In addition, IL-10 and TGF-beta secreted by Tr1 cells skew the antibody production from immunoglobulin E (IgE) towards the non-inflammatory isotypes IgG4 and IgA, respectively. Induction of antigen-specific Tr1 cells can thus re-direct an inappropriate immune response against allergens or auto-antigens using a broad range of suppressor mechanisms.     

Maternal serum interleukin-10, interleukin-2 and interleukin-6 in pre-eclampsia and eclampsia

PROBLEM: The aim of the study was to investigate and compare the concentrations of interleukin (IL)-2, IL-6, and IL-10 in serum of women with mild pre-eclampsia, severe pre-eclampsia, eclampsia, and normotensive pregnancy. METHOD OF STUDY: A total of 69 consecutive cases, 38 mild pre-eclampsia, 20 severe pre-eclampsia, 11 eclampsia, and 20 normotensive controls were included in this study. Serum IL-2, IL-6, and IL-10 levels were determined using enzyme-linked immunosorbent assay method. RESULTS: Gestational age (P = 0.210) and body mass index (P = 0.214) between the groups were similar. The mean concentration of serum IL-2 and IL-6 were not different between the groups (P = 0.261, P = 0.141 respectively). The median concentrations of serum IL-10 in patients with mild and severe pre-eclampsia were similar (P < 0.282) and was significantly lower than those of controls (P < 0.001) and patients with eclampsia (P < 0.001). In patients with eclampsia, the median concentration of IL-10 was significantly higher than that of all other groups (P < 0.001 for each comparison). CONCLUSION: Pre-eclampsia is associated with a deficiency serum IL-10. High serum IL-10 is correlated with the presence of eclampsia.     

Depression,traumatic stress and interleukin-6

BackgroundRecent evidence indicates that various types of interactions between nervous and immune system are important in pathogenesis of depression. These findings show that a significant role in developing depression play pro-inflammatory cytokines that may mediate its psychological, and neurobiological manifestations. Great importance among these cytokine molecules plays interleukin-6 (IL-6). There is growing evidence that this inflammatory process related to depression may be influenced by psychological stress as well as organic inflammatory conditions. These findings suggest that specific influences related to traumatic stress and dissociation could be found in close relationship to increased level of cytokine IL-6.MethodsIn the present study we have performed psychometric measurement of depression (BDI-II), traumatic stress symptoms (TSC-40) and dissociation (DES, SDQ-20), and immunochemical measure of serum IL-6 in 40 inpatients with unipolar depression (mean age 42.3 ± 6.8).ResultsThe results show that IL-6 is significantly correlated to BDI-II (Spearman R = 0.47, p < 0.01), TSC-40 (Spearman R = 0.32, p < 0.05), SDQ-20 (Spearman R = 0.34, p < 0.05) but not to DES (Spearman R = 0.25, p = 0.11).ConclusionThe findings of the present study indicate that increased level of IL-6 in depression could be directly related to symptoms of traumatic stress and somatoform dissociation.     

The mycotoxins citrinin and gliotoxin differentially affect production of the pro-inflammatory cytokines tumour necrosis factor-α and interleukin-6, and the anti-inflammatory cytokine interleukin-10

BACKGROUND: Microbial growth is considered one of the major causes of indoor air problems. Moulds have been associated with asthma, allergy and a wide range of diffuse indoor air-related symptoms. However, mechanisms of the adverse health effects are not well understood. OBJECTIVE: We hypothesized that the mycotoxins citrinin and gliotoxin could cause an imbalance between the secretion of the pro-inflammatory cytokines TNF-alpha and IL-6 and the anti-inflammatory cytokine IL-10. METHODS: We investigated the influence of citrinin and gliotoxin on the human monocytic cell line Mono-Mac-6 (MM6) with and without lipopolysaccharide -stimulation. The levels of IL-10, IL-6 and TNF-alpha were analysed in cell culture supernatants by ELISA. Cell viability and cell apoptosis were measured by flow cytometry. RESULTS: The strongest inhibition of cytokine secretion was found for IL-10. IL-6 levels were found to decrease in a dose-dependent manner along with reduced cell viability. TNF-alpha levels increased with low gliotoxin exposure (less than 100 ng/mL), but decreased significantly at 375 ng/mL and higher along with increased cell apoptosis and reduced cell viability. TNF-alpha levels were not reduced by citrinin exposure. CONCLUSION: We observed a cytokine imbalance with a more pronounced reduction of IL-10 concentrations compared with those of TNF-alpha and IL-6. We suggest that low exposure doses of citrinin and gliotoxin (corresponding to less than 100 ng/mL gliotoxin and less than 10 mug/mL citrinin) may inhibit IL-10 and lead to increased risk of an inflammatory response with relative overproduction of TNF-alpha and IL-6. The findings and their clinical implications must be verified by human studies. However, we speculate that the observed biological effects may be of importance as they may partly explain the occurrence of diffuse general indoor air-related symptoms as well as the worsening of asthmatic inflammatory reactions experienced in mouldy environments.     

Increased serum-soluble interleukin-2 receptor in burn patients: characterization and effects on the immune system

The consequences of high serum concentrations of the interleukin (IL)-2 receptor alpha chain (sIL-2Ralpha) in several diseases are poorly understood. The objective of this study was to determine the form of sIL-2Ralpha in burn patients and its biological role. sIL-2Ralpha was measured in 18 severely burned individuals who received nutritional support with a normal or low fat content. sIL-2Ralpha was elevated throughout the study and it was notably lower in patients fed a low fat diet. Serum IL-6 and sIL-2Ralpha significantly correlated (r = 0.74, p < 0.05) in burn patients. The presence of sIL-2Ralpha was associated with a decrease in DR molecules in the CD2(-) and CD11b(+) cells of these patients. Western blot analysis of serum protein with N-terminal or C-terminal specific antibodies indicated that sIL-2Ralpha represents the extracellular domain of this molecule. Patient serum inhibited specifically murine, but not human IL-2-dependent T-cell proliferation. To determine the significance of sIL-2Ralpha, recombinant sIL-2Ralpha was used in different cellular model involving IL-2. sIL-2Ralpha inhibited natural killer cell activity by 50% in the presence of IL-2. The basal proliferation of peripheral blood mononuclear cells was inhibited by sIL-2Ralpha, but phytohemagglutinin-induced proliferation was unaffected by this form of receptor. Interferon (INF)-gamma production induced by OKT-3 on peripheral blood mononuclear cells was not altered by sIL-2Ralpha, but IL-2 induced increase in INF-gamma production was suppressed. The decreasing production of INF-gamma in the presence of IL-4 was significantly increased in the presence of sIL-2Ralpha in media. These results show that the large amount of sIL2-Ralpha circulating in burn patients is related to the inflammatory response. The amount of dietary fat modulates sIL2Ralpha concentration in burn patients, confirming the beneficial effect of low fat administration after burn trauma. Inhibition of T-cell activation in burn patients is not directly related to sIL-2Ralpha, although the presence of sIL-2Ralpha in serum can inhibit some IL-2 mediated response, such as the emergence of TH1 and TH2 cells.     

Influences of anti-mouse interleukin-6 receptor antibody on immune responses in mice

In the present study, we examined the effect of anti-IL-6 receptor antibody (MR16-1) on humoral and cellular immune responses in mice. MR16-1 did not affect antigen-specific antibody production in either the primary or secondary response in mice immunized with dinitro-phenyl (DNP)-keyhole limpet haemocyanin (KLH) in saline. DNP-KLH immunization with complete Freund's adjuvant (CFA) markedly augmented anti-DNP antibody production and induced interleukin 6 (IL-6) production in serum. In this case, MR16-1 significantly suppressed antibody production and further increased serum IL-6 levels. Regarding the cellular response, we studied the effect on the delayed-type hypersensitivity (DTH) response. DTH response was induced in mice by the immunization with Mycobacterium butyricum with incomplete Freund's adjuvant and following antigen challenge into the footpad 14 days after immunization. When MR16-1 was injected immediately after immunization, the DTH response was significantly suppressed and enlargement of the spleen was also suppressed. This suppressive effect was observed, when MR16-1 was administered on day 0, but not on days 5 and 10. Again, serum IL-6 levels were much higher in MR16-1-treated mice compared with controls. Furthermore, spleen cells from control mice released IL-2 and INFgamma by the stimulation of antigen in vitro. In contrast, spleen cells from MR16-1-treated mice produced these cytokines at a marginal level. In contrast, MR16-1 did not suppress the DTH response, when it was injected immediately after antigen challenge. Our results suggest that IL-6 does not always involve antibody production, although IL-6 augments antibody production, and that IL-6 is essential for the induction of Th1 cells.     

Metabolic effects of interleukin-6 in human splanchnic and adipose tissue

Interleukin-6 (IL-6) was infused intravenously for 2.5 h in seven healthy human volunteers at a dose giving rise to a circulating IL-6 concentration of ≈35 ng l⁻¹. The metabolic effects of this infusion were studied in subcutaneous adipose tissue on the anterior abdominal wall and in the splanchnic tissues by the Fick principle after catheterizations of an artery, a subcutaneous vein draining adipose tissue, and a hepatic vein, and measurements of regional adipose tissue and splanchnic blood flows. In control studies without IL-6 infusion subcutaneous adipose tissue metabolism was studied by the same technique in eight healthy subjects. The net release of glycerol and fatty acids from the subcutaneous abdominal adipose tissue remained constant in the control experiment. IL-6 infusion gave rise to increase in net glycerol release in subcutaneous adipose tissue while the net release of fatty acids did not change significantly. In the splanchnic region IL-6 elicited a pronounced vasodilatation, and the uptake of fatty acids and the gluconeogenic precursors glycerol and lactate increased significantly. The splanchnic net output of glucose and triacylglycerol did not change during the IL-6 infusion. It is concluded that IL-6 elicits lipolytic effects in human adipose tissue in vivo , and that IL-6 also has effects on the splanchnic lipid and carbohydrate metabolism.     

IL-6 and APPs: anti-inflammatory and immunosuppressive mediators

Acute inflammation is accompanied by changes in the concentrations of acute phase proteins (APPs), While much is known about the cytokines involved in the initiation of inflammation, less is known about the mediators involved in its resolution. Recent data suggest that interleukin 6 (IL-6) and IL-6-regulated APPs are anti-inflammatory and immuno-suppressive, and may negatively regulate the acute phase response.     

Contrasting effects of interferon-gamma and interleukin-4 on the interleukin-6 activity of stimulated human monocytes.

Stimulated human monocytes/macrophages are a source of interleukin-6 (IL-6), which is a likely mediator involved in immune and inflammatory reactions. The means to control production of IL-6 by these cells could therefore have therapeutic applications. We report here, for lipopolysaccharide (LPS)-stimulated human monocytes in vitro, that the lymphokine, interferon-gamma (IFN-gamma) (100 U/ml), enhanced the level of IL-6 activity, whereas another lymphokine, interleukin-4 (IL-4) (greater than or equal to 0.1 U/ml; greater than or equal to 1.2 x 10(-11) M), suppressed it. The effects of the two lymphokines were manifested at the level of mRNA. The action of the IL-4 was similar to that of the glucocorticoid, dexamethasone, but observed at a lower molar concentration. Such regulation of monocyte IL-6 activity is similar to that found previously for interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha) synthesis.     

雌激素与IL-6、IL-8在卵巢癌细胞中的调节作用

目的 探讨雌激素与IL-6、IL-8在卵巢癌细胞中的交互调节作用及作用机制.方法 选择兼有雌激素受体(estrogen receptor,ER)及IL-6、IL-8受体表达的卵巢癌细胞系CAOV-3和OVCAR-3作为研究模型,分别探讨17B-雌二醇(estradiol,E2)对IL-6、IL-8及其受体表达的作用以及IL-6、IL-8对EB表达及ER转录活性的作用.结果 一方面E2不仅可经NF-κB途径促进卵巢癌细胞IL-6、IL-8分泌,而且还对二者受体的表达具有一定的调节作用.E2诱导的促IL-6、IL-8分泌作用可被其受体阻断剂他莫昔芬(tamoxifen,Txf)完全阻断.另一方面在无雌激素的条件下,IL-6、IL-8能上调卵巢癌细胞Erα表达及下调ERB表达,且还能分别通过丝裂原活化蛋白激酶(MAPK)信号通路和Src活化增强卵巢癌细胞ER的转录活性,该作用可被Txf完全封闭.结论 雌激素与IL-6、IL-8两种细胞因子在卵巢癌细胞中交互调节,由此通过产生的放大信号通路促进卵巢癌的生长和发展.