IL-23 and IL-17 in tuberculosis

Tuberculosis is a chronic disease requiring the constant expression of cellular immunity to limit bacterial growth. The constant expression of immunity also results in chronic inflammation, which requires regulation. While IFN-gamma-producing CD4+ T helper cells (Th1) are required for control of bacterial growth they also initiate and maintain a mononuclear inflammatory response. Other T cell subsets are induced by Mycobacterium tuberculosis (Mtb) infection including those able to produce IL-17 (Th17). IL-17 is a potent inflammatory cytokine capable of inducing chemokine expression and recruitment of cells to parenchymal tissue. Both the IL-17 and the Th17 response to Mtb are largely dependent upon IL-23. Although both Th17 and Th1 cells are induced following primary infection with Mtb, the protective response is significantly altered in the absence of Th1 cells but not in the absence of Th17. In contrast, in vaccinated animals the absence of memory Th17 cells results in loss of both the accelerated memory Th1 response and protection. Th1 and Th17 responses cross-regulate each other during mycobacterial infection and this may be important for immunopathologic consequences not only in tuberculosis but also other mycobacterial infections.     

IL-4-supported induction of cytolytic T lymphocytes requires IL-2 and IL-6

Previous work indicated that a CTL response can be generated by the combination of IL-2 plus IL-6 or IL-4 alone. Because of the ubiquitous production of IL-6 and its apparent ability to induce IL-2, we explored the interdependence of these lymphokines in supporting a CTL response from murine thymocytes. For thymocytes cultured in IL-4, further addition of IL-6 enhanced thymocyte proliferation. In addition, a role for IL-6 in thymocyte activation was indicated by the ability of anti-IL-6 mAb to block both IL-4-directed proliferation and the cytotoxic response found in the presence of IL-4. The addition of IL-2 to limiting doses of IL-4 augmented the CTL response; however, the response to high levels of IL-4 was not augmented by addition of IL-2. Consistent with this apparent involvement of IL-2 in the IL-4-mediated response we found: (a) that mAb to IL-2 significantly reduced the CTL response generated in the presence of IL-4; (b) that IL-2 activity was present in culture supernatant following incubation of thymocytes with high levels of IL-4; and (c) that enhanced IL-2 receptor expression found in the presence of IL-4 was blocked with the addition of anti-IL-2 antibody to the thymocyte culture. In contrast to the data for proliferation, anti-IL-4 mAb had no effect on the generation of CTL in the presence of IL-2 + IL-6 but readily blocked the CTL response to IL-4. These results indicate that, for thymocyte responders, the CD8+ CTL generated in the presence of IL-4 require both IL-2 and IL-6.     

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。     

Recombinant human interleukins IL-1alpha, IL-1beta, IL-4, IL-6, and IL-7 show different and specific calcium-independent carbohydrate-binding properties

A method was developed for the determination of putative lectin activities of cytokines. It involved the immunoblotting measurement of the quantity of these cytokines unbound to a series of different immobilized glycoconjugates and displacement of the bound cytokines with oligosaccharides of known structures. This method allows demonstrating that the following interleukins specifically recognize different oligosaccharide structures in a calcium-independent mechanism: interleukin-1alpha binds to the biantennary disialylated N-glycan completed with two Neu5Acalpha2-3 residues; interleukin-1beta to a GM4 sialylated glycolipid Neu5Acalpha2-3Galbeta1-Cer having very long and unusual long-chain bases; interleukin-4 to the 1,7 intramolecular lactone of N-acetyl-neuraminic acid; interleukin-6 to compounds having N-linked and O-linked HNK-1-like epitopes; and interleukin-7 to the sialyl-Tn antigen. Because the glycan ligands are rare structures in human circulating cells, it is suggested that such activities could be essential for providing specific signaling systems to cells having both the receptors and the oligosaccharide ligands of the interleukin at their cell surface.     

IL-12-and IL-23 in health and disease

Interleukin (IL)-12 and IL-23 play important roles in the development of experimental autoimmune disease models and numerous afflictions affecting humans. Preclinical data over the last 20 years combined with successful clinical trials has identified a clear relationship between IL-12, IL-23 and the generation of pathogenic T helper cells capable of orchestrating tissue inflammation. Observations made in the clinic have shown that IL-12p40, a common subunit shared by IL-12 and IL-23, is critical to pathologies associated with psoriasis, inflammatory bowel disease (IBD) and tumor growth. These advancements have set in motion the development of a number of potential therapeutics aimed at manipulating IL-12/23 signaling pathways in both mice and humans. This review will discuss a brief history of the understanding and expansion of the IL-12 cytokine family, some difficulties associated with preclinical data interpretation and finally the medicinal interventions that have been developed to combat IL-12/23-driven autoimmune disorders.     

IL-18/IL-18BP and IL-22/IL-22BP: Two interrelated couples with therapeutic potential

Interleukin (IL)-18 and IL-22 are key components of cytokine networks that play a decisive role in (pathological) inflammation, host defense, and tissue regeneration. Tight regulation of cytokine-driven signaling, inflammation, and immunoactivation is supposed to enable nullification of a given deleterious trigger without mediating overwhelming collateral tissue damage or even activating a cancerous face of regeneration. In fact, feedback regulation by specific cytokine opponents is regarded as a major means by which the immune system is kept in balance. Herein, we shine a light on the interplay between IL-18 and IL-22 and their opponents IL-18 binding protein (IL-18BP) and IL-22BP in order to provide integrated information on their biology, pathophysiological significance, and prospect as targets and/or instruments of therapeutic intervention.     

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.     

Circulating IL-6, IL-10, and TNF-alpha and IL-10/IL-6 and IL-10/TNF-alpha ratio profiles of polyparasitized individuals in rural and urban areas of gabon

Malaria, blood-borne filarial worms and intestinal parasites are all endemic in Gabon. This geographical co-distribution leads to polyparasitism and, consequently, the possibility of immune-mediated interactions among different parasite species. Intestinal protozoa and helminths could modulate antimalarial immunity, for example, thereby potentially increasing or reducing susceptibility to malaria. The aim of the study was to compare the cytokine levels and cytokine ratios according to parasitic profiles of the population to determine the potential role of co-endemic parasites in the malaria susceptibility of populations. Blood and stool samples were collected during cross-sectional surveys in five provinces of Gabon. Parasitological diagnosis was performed to detect plasmodial parasites, Loa loa, Mansonella perstans, intestinal helminths (STHs) and protozoan parasites. Nested PCR was used to detect submicroscopic plasmodial infection in individuals with negative blood smears. A cytometric bead array was used to quantify interleukin (IL)-6, IL-10 and tumour necrosis factor (TNF)-α in the plasma of subjects with different parasitological profiles. Median IL-6 and IL-10 levels and the median IL-10/TNF-α ratio were all significantly higher among individuals with Plasmodium (P.) falciparum infection than among other participants (p<0.0001). The median TNF-α level and IL-10/IL-6 ratio were higher in subjects with STHs (p = 0.09) and P. falciparum-intestinal protozoa co-infection (p = 0.04), respectively. IL-6 (r = -0.37; P<0.01) and IL-10 (r = -0.37; P<0.01) levels and the IL-10/TNF-α ratio (r = -0.36; P<0.01) correlated negatively with age. Among children under five years old, the IL-10/TNF-α and IL-10/IL-6 ratios were higher in those with intestinal protozoan infections than in uninfected children. The IL-10/TNF-α ratio was also higher in children aged 5–15 years and in adults harbouring blood-borne filariae than in their control counterparts, whereas the IL-10/IL-6 ratio was lower in those aged 5–15 years with filariae and intestinal parasites but higher in adults with intestinal parasitic infections. Asymptomatic malaria is associated with a strong polarization towards a regulatory immune response, presenting high circulating levels of IL-10. P. falciparum/intestinal protozoa co-infections were associated with an enhanced IL-10 response. Immunity against malaria could differ according to age and carriage of other parasites. Helminths and intestinal protozoa can play a role in the high susceptibility to malaria currently observed in some areas of Gabon, but further investigations are necessary.     

IL-6 and IL-1 synergize to stimulate IL-2 production and proliferation of peripheral T cells

Purified T cells can be induced to proliferate and to produce the autocrine growth factor IL-2 with mAb to the TCR and costimulatory cytokines. In a previous report we demonstrated that human IL-6 stimulates IL-2 production and proliferation of purified T cells, in conjunction with the insolubilized anti-TCR V beta 8 mAb, F23.1. Here we show that when CD4+ T cells are rigorously purified to greater than 99% CD4+CD8-, they respond only weakly to F23.1 and IL-6. Instead, there is an additional requirement for IL-1, which dramatically synergizes with IL-6 to induce prolonged (greater than 7 days) proliferative responses and IL-2 production. Similar results were observed when the highly mitogenic anti-CD3 mAb 145-2C11 was substituted for F23.1. The proliferation induced by F23.1, IL-1, and IL-6 was substantially (greater than 80%) inhibited by a mAb to mouse IL-2, and was not inhibited by an anti-IL-4-mAb. In accordance with this finding, medium conditioned by the activated CD4+ cells contained large amounts of IL-2, which increased over a 7-day culture period. These results demonstrate that IL-6 and IL-1 stimulate T cell proliferation by inducing production of the autocrine growth factor IL-2. In addition, the two lymphokines must be present simultaneously for activation to occur. The possible roles of IL-6 and IL-1 in IL-2 gene regulation and in Ag-induced T cell activation are discussed.     

Integrated signals between IL-13, IL-4, and IL-5 regulate airways hyperreactivity

In this investigation, we have examined the integrated relationship between IL-13, IL-4, and IL-5 for the development of airways hyperreactivity (AHR) in a model of asthma in BALB/c mice. Sensitization and aeroallergen challenge of both wild-type (WT) and IL-13 gene-targeted (IL-13-/-) mice induced allergic disease that was characterized by pulmonary eosinophilia and AHR to beta-methacholine. Although these responses in IL-13-/- mice were heightened compared with WT, they could be reduced to the level in nonallergic mice by the concomitant neutralization of IL-4. Mice in which both IL-4 and IL-13 were depleted displayed a marked reduction in tissue eosinophils, despite the development of a blood eosinophilia. Similar neutralization of IL-4 in WT mice only partially reduced AHR with no effect on tissue eosinophilia. In addition, neutralization of IL-5 in IL-13-/- mice, but not in WT mice, inhibited AHR, suggesting that tissue eosinophilia is linked to the mechanism underlying AHR only in the absence of IL-13. Additionally, mucus hypersecretion was attenuated in IL-13-/- mice, despite the persistence of AHR. Taken together, our data suggest both a modulatory role for IL-13 during sensitization and a proinflammatory role during aeroallergen challenge. The latter process appears redundant with respect to IL-4.     

IL-10 and IL-4 regulate type-I and type-II IL-1 receptors expression on IL-1β-activated mouse primary astrocytes

When activated by its ligand, the interleukin receptor type I (IL-1RI) transduces signals in cooperation with the IL-1 receptor accessory protein (IL-1RacP). In contrast, IL-1RII functions as a decoy receptor without participating in IL-1 signalling. Brain astrocytes are cellular targets of IL-1 and play a pivotal role in brain responses to inflammation. The regulation of IL-1 receptors on astrocytes by anti-inflammatory cytokines such as IL-4 and IL-10 has not been studied, despite its importance for understanding the way these cells respond to IL-1. Using RT-PCR, we first showed that the expression of IL-1RI and IL-1RII, but not IL-1RacP, mRNAs are up-regulated by IL-1 beta in a time-dependent manner. Using a radioligand binding technique, we then showed that astrocytes display an equivalent number of IL-1RI and IL-1RII. IL-1 beta decreases the number of IL-1RI binding sites, whereas it increases those of IL-1RII. IL-4 and IL-10 both up-regulate IL-1RII IL-1 beta-induced, but only IL-4 does so for IL-1RI. At the protein level, IL-4 and IL-10 dramatically reverse the ability of IL-1 beta to inhibit expression of IL-1RI but neither affects the ability of IL-1 beta to enhance the number of IL-1RII. Collectively, these results establish the existence of receptor cross-talk between pro- and anti-inflammatory cytokines on a critical type of cell that regulates inflammatory events in the brain.     

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.     

Structures and biological functions of IL-31 and IL-31 receptors

Interleukin-31, produced mainly by activated CD4⁺ T cells, is a newly discovered member of the gp130/IL-6 cytokine family. Unlike all the other family members, IL-31 does not engage gp130. Its receptor heterodimer consists of a unique gp130-like receptor chain IL-31RA, and the receptor subunit OSMRβ that is shared with another family member oncostatin M (OSM). Binding of IL-31 to its receptor activates Jak/STAT, PI3K/AKT and MAPK pathways. IL-31 acts on a broad range of immune- and non-immune cells and therefore possesses potential pleiotropic physiological functions, including regulating hematopoiesis and immune response, causing inflammatory bowel disease, airway hypersensitivity and dermatitis. This review summarizes the recent findings on the biological characterization and physiological roles of IL-31 and its receptors.     

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.     

Differential regulation by IL-4 and IL-10 of radiation-induced IL-6 and IL-8 production and ICAM-1 expression by human endothelial cells.

Radiation exposure results in an inflammatory reaction with acute as well as subacute consequences. Leukocyte infiltration is one of the predominant early histological changes and involves both cytokines and adhesion molecules. Endothelial cells play a key role in this reaction. We have previously shown the increased production of interleukin 6 (IL-6) and IL-8 and the upregulation in intercellular adhesion molecule 1 (ICAM-1) expression by HUVEC following gamma ray exposure. In the present study, we used the cytokines IL-4 and IL-10 to regulate these radiation-induced manifestations. Human umbilical vascular endothelial cells (HUVEC) were treated with IL-4 and IL-10 (50 pg/ml) either before or after 10- Gy irradiation. Three and seven days after irradiation, IL-6 and IL-8 production by HUVEC (either treated or non-treated) was assessed by enzyme-linked immunosorbent assay (ELISA). Our results show that IL-4, when added after irradiation, reversed the radiation-induced increase in IL-8 production, although slightly increased IL-6 production. IL-10 decreased both IL-8 and IL-6 production when added after irradiation. ICAM-1 expression was evaluated 3 days after irradiation by flow cytometry. The radiation-induced upregulation in ICAM-1 expression remained unaffected by the use of IL-4. Altogether, our results show that radiation-induced endothelial cell activation may be ameliorated by IL-4 and/or IL-10, which is of significance in designing strategies for cytokine-mediated intervention and/or therapy of radiation damage.     

Synergistic anti-tumor effect of glycosylphosphatidylinositol-anchored IL-2 and IL-12

BACKGROUND: Preclinical and clinical studies have demonstrated that interleukin 2 (IL-2), interleukin 12 (IL-12), and some other cytokines, play important roles in activating host immune responses against tumor growth. However, severe side effects caused by systemic high-dose administration of these cytokines limit their clinical application. In our previous study, local high doses of IL-2 were achieved by a GPI-anchoring technology; therefore, it will be interesting to know if this technology works for other cytokines. METHODS: A fusion gene containing murine IL-12 and the glycosylphosphatidylinositol (GPI) anchor signal sequence was generated and transfected into the murine melanoma tumor cell line B16F0 either alone or together with a vector encoding GPI-anchored IL-2. The GPI-anchored cytokine expression of the selected stable clones was assayed in vitro by ELISA and their anti-tumor effects were analyzed in vivo by tumor lymphocyte infiltration and tumor growth studies. RESULTS: GPI-anchored IL-12 was successfully expressed on the cell surface as indicated by FACS analysis and IL-12 ELISA assay. The GPI-anchored IL-12 enhanced lymphocyte infiltration and significantly inhibited tumor growth. More importantly, when GPI-anchored IL-12 and GPI-anchored IL-2 were co-delivered, a synergistic anti-tumor effect was observed in both subcutaneous and intravenous tumor models. CONCLUSIONS: GPI anchorage of cytokines represents a new approach to locally deliver high doses of cytokines without the severe adverse effects normally accompanied with systematic high-dose administration of these cytokines.