Genetic loci on chromosome 5 are associated with circulating levels of interleukin-5 and eosinophil count in a European population with high risk for cardiovascular disease

IL-5 is a Th2 cytokine which activates eosinophils and is suggested to have an atheroprotective role. Genetic variants in the IL5 locus have been associated with increased risk of CAD and ischemic stroke. In this study we aimed to identify genetic variants associated with IL-5 concentrations and apply a Mendelian randomisation approach to assess IL-5 levels for causal effect on intima-media thickness in a European population at high risk of coronary artery disease. We analysed SNPs within robustly associated candidate loci for immune, inflammatory, metabolic and cardiovascular traits. We identified 2 genetic loci for IL-5 levels (chromosome 5, rs56183820, BETA = 0.11, P = 6.73E−5 and chromosome 14, rs4902762, BETA = 0.12, P = 5.76E−6) and one for eosinophil count (rs72797327, BETA = −0.10, P = 1.41E−6). Both chromosome 5 loci were in the vicinity of the IL5 gene, however the association with IL-5 levels failed to replicate in a meta-analysis of 2 independent cohorts (rs56183820, BETA = 0.04, P = 0.2763, I2 = 24, I2 − P = 0.2516). No significant associations were observed between SNPs associated with IL-5 levels or eosinophil count and IMT measures. Expression quantitative trait analyses indicate effects of the IL-5 and eosinophil-associated SNPs on RAD50 mRNA expression levels (rs12652920 (r2 = 0.93 with rs56183820) BETA = −0.10, P = 8.64E−6 and rs11739623 (r2 = 0.96 with rs72797327) BETA = −0.23, P = 1.74E−29, respectively). Our data do not support a role for IL-5 levels and eosinophil count in intima-media thickness, however SNPs associated with IL-5 and eosinophils might influence stability of the atherosclerotic plaque via modulation of RAD50 levels

The effects of anti-sense interleukin-5 gene transferred by recombinant adeno-associated virus in allergic rats

The accumulation and infiltration of eosinophils in airways is one of the most important characteristics of asthma, and is mediated partly by secretion of IL-5 from Th2 lymphocytes. It is well known that interleukin-5 (IL-5) played an important role in the regulation of eosinophils. In this study, an anti-sense IL-5 gene transferred by recombinant adeno-associated virus (rAAV-ASIL-5) was prepared to transfect allergic rats. It was found that the expression of IL-5 protein in plasma and BALF were inhibited significantly. The rAAV-ASIL-5-mediated suppression of total cell counts in peripheral blood and BALF were also observed. Moreover, rAAV-ASIL-5 remarkably reduced the eosinophil counts in peripheral blood and BALF, as well as the expression of ECP protein in plasma and BALF. The inflammation in lungs of rAAV-ASIL-5 pretreated rats also became slighter when compared with allergic rats. Otherwise, no apparent pathological damage to vital organs of rats was found. In conclusion, recombinant adeno-associated virus-mediated delivery of anti-sense IL-5 gene inhibited the accumulation of eosinophils and the airways inflammation in rat model of allergic asthma via suppressing IL-5 expression. It suggested the feasibility of rAAV-ASIL-5 in the gene therapy for allergic asthma and other eosinophilic diseases

Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo.

Experiments were designed to study the effect of systemically administered IL-5 on local eosinophil accumulation induced by the intradermal injection of the chemokine eotaxin in the guinea pig. Intravenous interleukin-5 (IL-5) stimulated a rapid and dramatic increase in the numbers of accumulating eosinophils induced by i.d.-injected eotaxin and, for comparison, leukotriene B4. The numbers of locally accumulating eosinophils correlated directly with a rapid increase in circulating eosinophils: circulating eosinophil numbers were 13-fold higher 1 h after intravenous IL-5 (18.3 pmol/kg). This increase in circulating cells corresponded with a reduction in the number of displaceable eosinophils recovered after flushing out the femur bone marrow cavity. Intradermal IL-5, at the doses tested, did not induce significant eosinophil accumulation. We propose that these experiments simulate important early features of the tissue response to local allergen exposure in a sensitized individual, with eosinophil chemoattractant chemokines having an important local role in eosinophil recruitment from blood microvessels, and IL-5 facilitating this process by acting remotely as a hormone to stimulate the release into the circulation of a rapidly mobilizable pool of bone marrow eosinophils. This action of IL-5 would be complementary to the other established activities of IL-5 that operate over a longer time course

Cytokine Profiles of Stimulated Blood Lymphocytes in Asthmatic and Healthy Adolescents Cross the School Year

T cell cytokines play an important role in mediating airway inflammation in asthma. The predominance of a Th2 cytokine profile, particularly interleukin (IL)-4 and IL-5, is associated with the pathogenesis and course of asthma. The aim of this study was to test the hypothesis that a stressful life event alters the pattern of cytokine release in asthmatic individuals. Thirteen healthy controls and 21 asthmatic adolescents gave blood samples three times over a semester: midsemester, during the week of final examinations, and 2-3 weeks after examinations. Interferon-γ (IFN-γ), IL-2, IL-4, and IL-5 were measured from supernatants of cells stimulated with PHA/PMA for 24 h. Cells from asthmatic subjects released significantly more IL-5 during the examination and postexamination periods, whereas cells from healthy controls released significantly more IL-2 during the midsemester and examination periods, thereby indicating a bias for a Th2-like pattern in asthmatics and a Th 1-like pattern in healthy controls. IL-4 and IL-5 production showed a marked decrease during and after examinations in healthy controls, whereas this decline was absent in asthmatics. The ratios of IFN-γ:IL-4 and IFN-γ:IL-5 also revealed significant changes in the profile of cytokine release across the semester. These results indicate differential cytokine responses in asthmatics that may become pronounced during periods of cellular activation

Faculty Recital: Tong-Il Han, piano, November 5, 2002

This is the concert program of the Faculty Recital: Tong-Il Han, piano performance on Tuesday, November 5, 2002 at 8:00 p.m., at the Tsai Performance Center, 685 Commonwealth Avenue. Works performed were Melody from the opera "Orfeo ed Euridice" by Christoph Willibald von Gluck, Four Preludes by Sergei Rachmaninov, Sonata No. 6 in A Major, Op. 82 by Sergei Prokofiev, and Four Ballades by Frédéric Chopin. Digitization for Boston University Concert Programs was supported by the Boston University Humanities Library Endowed Fund

Immune Responses in Human Necatoriasis: Association between Interleukin-5 Responses and Resistance to Reinfection

Cytokine and proliferative responses to Necator americanus infection were measured in a treatment-reinfection study of infected subjects from an area of Papua New Guinea where N. americanus is highly endemic. Before treatment, most subjects produced detectable interleukin (IL)4 (97%), IL-5 (86%), and interferon (IFN)-γ(64%) in response to adult N. americanus antigen. Pretreatment IFN-γ responses were negatively associated with hookworm burden, decreasing by 18 pg/mL for each increase of 1000 eggs/gram (epg) (n = 75; P < .01). Mean IFN-γ responses increased significantly after anthelmintic treatment, from 166 to 322 pg/mL (n = 42; P < .01). The intensity of reinfection was significantly negatively correlated with pretreatment IL-5 responses, decreasing by 551 epg for each 100 pg/mL increase in production of IL-5 (n = 51; P < .01). These data indicate that there is a mixed cytokine response in necatoriasis, with worm burdenassociated suppression of IFN-γ responses to adult N. americanus antigen. Resistance to reinfection is associated with the parasite-specific IL-5 response

Mediators and Cytokines in Persistent Allergic Rhinitis and Nonallergic Rhinitis with Eosinophilia Syndrome

Background: Patients with nonallergic rhinitis with eosinophilia syndrome (NARES) show typical symptoms of persistent allergic rhinitis (PAR). The aim of the present study was to compare nasal cytokine patterns between NARES and PAR. Methods: Nasal secretions of 31 patients suffering from NARES, 20 patients with PAR to house dust mite and 21 healthy controls were collected using the cotton wool method and analyzed for interleukin (IL)-1 beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 beta (MIP-1 beta) by Bio-Plex Cytokine Assay as well as eosinophil cationic protein (ECP) and tryptase by UniCAP-FEIA. Results: NARES and PAR presented elevated levels of tryptase, while ECP was markedly increased solely in NARES compared to both the controls and PAR. Elevated levels of IL-1 beta, IL-17, IFN-gamma, TNF-alpha and MCP-1 were found in NARES compared to the controls as well as PAR. MIP-1 beta was elevated in NARES and PAR, while IL-4, IL-6 and G-CSF showed increased levels in NARES, and IL-5 was elevated in PAR only. Conclusions: In patients with NARES and PAR, eosinophils and mast cells appear to be the pivotal cells of inflammation, reflected by high levels of tryptase and ECP as well as IL-5 and GM-CSF as factors for eosinophil migration and survival. The elevated levels of proinflammatory cytokines in NARES may indicate the chronic, self-perpetuating process of inflammation in NARES which seems to be more pronounced than in PAR. IL-17 might be a factor for neutrophilic infiltration or be responsible for remodeling processes in NARES. Copyright (C) 2012 S. Karger AG, Base

Heterogeneity of helper/inducer T lymphocytes. II. Effects of interleukin 4- and interleukin 2-producing T cell clones on resting B lymphocytes.

To compare the helper function of murine T cell clones that secrete IL-2 and IFN-gamma (Th1 cells) or IL-4 and IL-5 (Th2), purified resting B cells were stimulated with F(ab')2 rabbit anti-mouse Ig (RAMG) and rabbit Ig-specific, class II MHC-restricted cloned T cells belonging to the two subsets. Both Th2 clones examined induced strong proliferative responses of B cells in the presence of RAMG, as well as the secretion of IgM and IgG1 antibodies. In contrast, the Th1 clones tested failed to stimulate B cell growth or antibody secretion. Th2-mediated B cell activation was dependent on IL-4 and IL-5, and was also inhibited by IFN-gamma or IFN-gamma produced by Th1 cells present in the same cultures. However, the failure of Th1 cells to help resting B cells could not be reversed with neutralizing anti-IFN-gamma antibody. In addition to this inhibitory effect, IFN-gamma was required for the secretion of IgG2a antibody, particularly when B cells were stimulated with polyclonal activators such as LPS. Finally, both sets of T cell clones secreted lymphokines when stimulated with purified B cells and RAMG. These experiments demonstrate that T cells that differ in lymphokine production also differ in their ability to help B cells as a result of cognate interactions at low concentrations of antigens. Moreover, IL-4, IL-5, and IFN-gamma serve different roles in the T cell-dependent proliferative and differentiative responses of resting B lymphocytes

MicroRNA regulation of type 2 innate lymphoid cell homeostasis and function in allergic inflammation.

MicroRNAs (miRNAs) exert powerful effects on immunity through coordinate regulation of multiple target genes in a wide variety of cells. Type 2 innate lymphoid cells (ILC2s) are tissue sentinel mediators of allergic inflammation. We established the physiological requirements for miRNAs in ILC2 homeostasis and immune function and compared the global miRNA repertoire of resting and activated ILC2s and T helper type 2 (TH2) cells. After exposure to the natural allergen papain, mice selectively lacking the miR-17∼92 cluster in ILC2s displayed reduced lung inflammation. Moreover, miR-17∼92-deficient ILC2s exhibited defective growth and cytokine expression in response to IL-33 and thymic stromal lymphopoietin in vitro. The miR-17∼92 cluster member miR-19a promoted IL-13 and IL-5 production and inhibited expression of several targets, including SOCS1 and A20, signaling inhibitors that limit IL-13 and IL-5 production. These findings establish miRNAs as important regulators of ILC2 biology, reveal overlapping but nonidentical miRNA-regulated gene expression networks in ILC2s and TH2 cells, and reinforce the therapeutic potential of targeting miR-19 to alleviate pathogenic allergic responses