The relationship between B-cell lymphoma 2, interleukin-1β, interleukin-17, and interleukin-33 and the development of diabetic nephropathy

Molecular Biology Reports - Diabetic nephropathy (DN) is among the main complications of diabetes mellitus and has been a major factor of renal failure. This study was designed to address the...     

Association between polymorphisms in interleukin-4Rα and interleukin-13 and glioma risk: A meta-analysis

Introduction: It has been suggested that allergies are inversely associated with glioma risk. Single nucleotide polymorphisms in two allergy-related genes [interleukin (IL)-4Rα, IL-13] have been implicated in susceptibility to glioma; however, results from the published studies remained inconclusive. Methods: To derive a more precise relationship, we conducted a meta-analysis including seven case–control studies that investigated the influence of IL-4Rα rs1801275 and IL13 rs20541 polymorphisms on glioma risk. Data were extracted from these studies and pooled odds ratios (OR) with 95% confidence intervals (CI) were used to investigate the strength of the association. Results: Overall, the pooled analysis showed that there was no significant association between the IL-4Rα rs1801275 polymorphism and glioma risk (OR = 0.99, 95%CI: 0.79–1.25, AG/GG vs. AA). However, we found that the IL13 rs20541 variant genotypes (GA/AA) were significantly associated with reduced risk for glioma (OR = 0.85, 95%CI: 0.75–0.97, GA/AA vs. GG). In the stratified analyses by ethnicity, marginally significant association between the IL13 rs20541 polymorphism and decreased glioma risk was found among Asian populations in dominant models (OR = 0.84, 95%CI: 0.70–1.00, GA/AA vs. GG). Conclusions: This meta-analysis suggests that the IL13 rs20541 but not the IL-4Rα rs1801275 polymorphism may be a genetic predictor for glioma. More studies with larger sample size are warranted to further elucidate the impact of the IL13 rs20541 polymorphism on glioma risk.     

Is interleukin-17 a proatherogenic biomarker?

The importance of chronic inflammation in atherogenesis and cytokine involvement in all stages of atherosclerotic plaque development is now obvious. Our approach of the significant cytokines involved in atherogenesis or cardiovascular diseases is based on a correlation between clinical research and experiments on animal models. The contribution of IL-17 in atherogenesis remains controversial. In this study we investigated the role of IL-17 in cardiovascular diseases and in atherosclerosis associated with pathological aging. We performed a case-control study, enrolling subjects aged over 65 years in both groups. We included 40 patients with cardiovascular disorders and 10 healthy volunteers. IL-17 levels were measured in the serum of patients and healthy controls, along with serum total cholesterol and triglycerides. Significantly higher levels of IL-17 were obtained in patients compared to healthy controls (p<0.001). The level of this biomarker correlated significantly with two biochemical parameters - serum total cholesterol and triglycerides (the Pearson coefficient showed statistical significance, p=0.033, respectively p=0.043). We did not find any correlation between IL-17 and these two parameters in the control group. Our study is useful in understanding the physiopathological implications of IL-17 in the atherogenesis process. This could represent a starting point for future studies, including research regarding the therapeutic potential of IL-17 in pathological aging.     

T cells redirected to interleukin-13Rα2 with interleukin-13 mutein–chimeric antigen receptors have anti-glioma activity but also recognize interleukin-13Rα1

Background aimsOutcomes for patients with glioblastoma remain poor despite aggressive multimodal therapy. Immunotherapy with genetically modified T cells expressing chimeric antigen receptors (CARs) targeting interleukin (IL)13Rα2, human epidermal growth factor receptor 2, epidermal growth factor variant III or erythropoietin-producing hepatocellular carcinoma A2 has shown promise for the treatment of glioma in preclinical models. On the basis of IL13Rα2 immunotoxins that contain IL13 molecules with one or two amino acid substitutions (IL13 muteins) to confer specificity to IL13Rα2, investigators have constructed CARS with IL13 muteins as antigen-binding domains. Whereas the specificity of IL13 muteins in the context of immunotoxins is well characterized, limited information is available for CAR T cells.MethodsWe constructed four second-generation CARs with IL13 muteins with one or two amino acid substitutions, and evaluated the effector function of IL13-mutein CAR T cells in vitro and in vivo.ResultsT cells expressing all four CARs recognized IL13Rα1 or IL13Rα2 recombinant protein in contrast to control protein (IL4R) as judged by interferon-γ production. IL13 protein produced significantly more IL2, indicating that IL13 mutein–CAR T cells have a higher affinity to IL13Rα2 than to IL13Rα1. In cytotoxicity assays, CAR T cells killed IL13Rα1- and/or IL13Rα2-positive cells in contrast to IL13Rα1- and IL13Rα2-negative controls. Although we observed no significant differences between IL13 mutein–CAR T cells in vitro, only T cells expressing IL13 mutein–CARs with an E13K amino acid substitution had anti-tumor activity in vivo that resulted in a survival advantage of treated animals.ConclusionsOur study highlights that the specificity/avidity of ligands is context-dependent and that evaluating CAR T cells in preclinical animal model is critical to assess their potential benefit.     

Is interleukin-6 the necessary pyrogenic cytokine?

(1) This paper analyses arguments suggesting a critical role for interleukin-6 (IL-6) in the manifestation of fever.

(2) Evidence supporting such a role for IL-6 derives from the excellent correlation between IL-6 in plasma and the accompanying fever, from neutralization experiments with anti-IL-6-antibodies, and from studies in IL-6-deficient mice.

(3) Peripherally administered IL-6 has rather poor pyrogenic properties and needs co-factors to elicit pronounced fever.

(4) Circumventricular organs, which lack a tight blood–brain barrier, have been identified as brain sites where circulating IL-6 causes a direct genomic activation of cellular elements in astrocytes and endothelial cells.

(5) Due to the fact that the onset of fever frequently preceeds the formation of sufficient amounts of IL-6 and the activation of brain cells by this cytokine, it is suggested that IL-6 contributes to the maintenance rather than to the induction of the initial phase of fever.

(6) During the time course of fever IL-6 seems to be involved in the induction of endogenous anti-inflammatory/antipyretic mediators and thus in the manifestation of defervescence.     

Limited tryptic digestion of recombinant human interleukin-2: Structure-binding relationships with the α chain of the interleukin-2 receptor

The surface topography and structural features of interleukin-2 (IL-2) in relation to its interaction with the α subunit of its receptor (IL-2Rα) have been probed by limited tryptic digestion followed by detailed structural analyses. Four sensitive cleavage sites in IL-2 (Lys⁸, Lys⁹, Lys³⁵, and Arg³⁸) were identified as surface amino acids, suggesting that they are potential binding sites for IL-2Rα. To examine the involvement of these residues in IL-2Rα binding, a truncated IL-2 molecule lacking the amino-terminal residues through Arg³⁸ was generated and it was found to be incapable of binding IL-2Rα in a solid-phase receptor binding sequencing assay. These studies have led to the conclusion that the IL-2Rα contact region of IL-2 includes residues Lys³⁵ and Arg³⁸. This finding is supported by the refined three-dimensional structure of IL-2 in which these residues are located outside of the compact bundle of four helices and thus are readily available for interaction with IL-2Rα.     

Changes of glycosylation of serum proteins in Sjögren's syndrome: correlation with interleukin-6 and soluble interleukin-2 receptor

A strong increase of the affinity for concanavalin A (Con A) of serum alpha 2-macroglobulin, a non-acute-phase protein, was observed by lectin blotting in patients with Sj?gren's syndrome (SS). On the contrary, the total Con A reactivity of serum proteins, measured by enzyme-linked lectin assay, was not augmented in SS, compared with normal donors, probably because positive changes of certain proteins were balanced by negative changes of others, as suggested by lectin blotting analysis. However, a significant increase of total Con A reactivity occurred in subjects with increased serum concentrations of soluble interleukin (IL)-2 receptor, compared with patients with normal concentrations of this marker of disease activity. On the other hand, the same parameter did not appear to be different in patients with normal or increased serum concentrations of IL-6, indicating that this cytokine was not probably responsible for the changes of glycosylation described here.     

A recombinant human interleukin-1β protects adriamycin-induced toxicity

Pretreatment with recombinant human interleukin-1β (IL-1) protected normal BALB/c mice from the lethal effect adriamycin (ADM) of related to dose and frequency of administration. Posttreatment with IL-1 failed to protect. Neutrophil and platelet counts after the administration of ADM (16mg/kg) did not differ between the group with and that without IL-1 pretreatment, whereas lipid peroxide levels in the heart were reduced in the group pretreated with IL-1. It appears that the chemoprotection mechanism of IL-1 lies in the prevention of cardiotoxicity due to ADM-induced free radicals.     

Is interleukin-18 associated with polycystic ovary syndrome?

Background  

Recent research show that polycystic ovary syndrome (PCOS) may have an association with low-grade chronic inflammation, IL-18 is considered as a strong risk marker of inflammation.     

Glial localization of interleukin-1α in invertebrate ganglia

1. Mytilus pedal ganglion contains a small population of glial cells that are immunopositive for interleukin-1 alpha. Positively stained fibers can also be seen in the neuropil of these sections. 2. The marine worm Nereis diversicolor also exhibits positive neural immunostaining for interleukin-1 alpha. 3. Both organisms contain hemocytes that contain immunoactivity for interleukin-1 alpha. The study suggests interleukin-1 alpha to be an ancient cytokine given its presence in organisms that evolved significantly earlier than mammals.     

Role of interleukin-1β, interleukin-6 and macrophage inflammatory protein-1β in prostaglandin-E2-induced hyperthermia in rats

The purpose of this study was to investigate the role of pyrogenic cytokines, such as IL-1β, IL-6 and MIP-1β, in the mechanisms underlying the hyperthermic response of rats to central injection of PGE₂. Thus, specific murine neutralizing antibodies against these cytokines were microinjected directly into the anterior hypothalamic, preoptic area (AH/POA) of unrestrained rats just before intracerebroventricular injection of PGE₂. The significant hyperthermia induced by PGE₂ was markedly suppressed by micro-injection of anti-IL-6 and partially attenuated by anti-IL-1β. However, the micro-injection of anti-MIP-1β failed to alter the hyperthermic response. The results indicate that PGE₂-induced hyperthermia is presumably mediated through actions of IL-6 on the thermosensitive cells of the AH/POA and confirm that distinct and alternate pathways exist in the rat brain for the induction of fever.     

Interferon-α and interleukin-12 gene therapy of cancer: interferon-α induces tumor-specific immune responses while interleukin-12 stimulates non-specific killing

Cytokine gene therapy is applied in clinical studies of tumors, and IFN-alpha and IL-12 are widely used for cancer immunotherapy. Using a poorly immunogenic murine colorectal cancer cell line, MC38, we compared antitumor effects of IFN-alpha and IL-12. Transduced MC38 cell lines expressing IFN-alpha or IL-12 (MC38-IFNalpha or MC38-IL12, respectively) were established using retroviral vectors. Transduction of IFN-alpha or IL-12 gene to MC38 cells significantly reduced tumorigenicity in immunocompetent mice. When tumor-free mice initially injected with MC38-IFNalpha or MC38-IL12 cells were reinjected contralaterally with wild-type MC38 cells (MC38-WT) after 35 days, 7 of 12 or 2 of 12 mice rejected MC38-WT cells, respectively. In therapy-model mice with established tumor derived from MC38-WT cells, inoculation of gene-transduced cells significantly suppressed growth of the tumor in MC38-IFNalpha-inoculated groups, but not in the IL-12-inoculated group. Immunohistologic and flow cytometric analyses showed marked infiltration of CD8(+) cells in wild-type tumors of mice inoculated with IFN-alpha-expressing cells. Leukocyte-depletion experiments implicated CD8(+) T cells in tumor rejection induced by IFN-alpha-transduction; both CD8(+) T cells and natural killer cells were implicated in the more modest antitumor effect from IL-12 expression. To investigate induction of tumor-specific immune responses, we stimulated splenocytes from tumor-free mice twice in vitro with genetically modified MC38 cells. In vitro stimulations with MC38-IFNalpha cells induced definite MC38-specific lysis, but not stimulations with MC38-IL-12 cells. Injecting combination of MC38-IFNalpha and MC38-IL-12 cells caused an additive antitumor effect in the therapy model. These data suggested that IFN-alpha induces cytotoxic T lymphocytes and elicits long-lasting tumor-specific immunity, whereas IL-12 seems to stimulate non-specific killing. With additional refinements, combined IFN-alpha and IL-12 gene therapy might warrant clinical trials.     

Endogenous ADP-ribosylation of elongation factor-2 by interleukin-1��

Eukaryotic elongation factor-2 (eEF-2) catalyses the motion of the growing peptide chain relative to the mRNA at the ribosomes during protein synthesis. This highly conserved G-protein is the specific target of two lethal bacterial toxins, Pseudomonas aeruginosa exotoxin A and diphtheria toxin. These toxins exert their detrimental action by ADP-ribosylating a biologically unique posttranslationally modified histidine residue (diphthamide(715)) within eEF-2, thus inactivating the enzyme. Diphthamide(715) is also the target of endogenous (mono) ADP-ribosyl transferase activity. In this article, we report the first known activator of endogenous ADP-ribosylation of eEF-2, interleukin-1β (IL-1β). Thereby, systemic inflammatory processes may link to protein synthesis regulation.     

Polymorphic tandem repeat region in interleukin-1α intron 6

Analysis of polymerase chain reaction amplified products from the sixth intron of the human interleukin-1 gene reveals a high polymorphism (polymorphism information content = 0.51) in a Caucasian population. Altogether, seven alleles have been defined ranging from 620 to 1220bp. This polymorphism is probably attributable to a variable number of 46-bp tandem repeats, each containing potential regulatory sequences.