- Email: [email protected]
PS2-049. Enhanced plasma Interleukin-1 activity contributes to cardiac dysfunction in heart failure
76
Abstract / Cytokine 56 (2011) 71–77
PS2-049 Enhanced plasma Interleukin-1 activity contributes to cardiac dysfunction in heart failure Benjamin Van Tassell, Stefano Toldo, Eleonora Mezzaroma, Norbert Voelkel, Antonio Abbate, Virginia Commonwealth University
PS2-051 Colchicine inhibits the activation of inflammasomes-mediated caspases-1, but not the IL-1b production Min-yeong Woo, Okki Cho, Mi Jin Lee, Eun-So Lee, Sun Park, Dept. of Microbiology, Ajou University School of Medicine, Suwon, Korea
Background. Heart failure (HF) is a complex clinical syndrome characterized by impaired cardiac function and poor exercise tolerance. Enhanced inflammation is associated with worsening outcomes in HF patients and may play a direct role in disease progression. Interleukin-1 (IL-1) is a pro-inflammatory cytokine that becomes chronically elevated in HF and exerts putative negative inotropic effects. We hypothesized that the IL-1 activity in the plasma from HF patients would be sufficient to reproduce a phenotype of cardiac dysfunction in healthy mice. Methods. We collected blood from four groups of patients based upon HF symptoms and high sensitivity C-reactive protein (hsCRP, a surrogate marker of IL-1 activity): healthy controls (CTRL), ambulatory HF patients with low CRP (HF L-CRP), ambulatory HF with high CRP (HF H-CRP), and patients hospitalized for acute decompensated HF (ADHF). Plasma samples from each group were injected into healthy mice with transthoracic echocardiography to measure left ventricular (LV) function at baseline and 4 hours. Upon completion of echocardiography at 4 hours, all groups of mice received an injection of isoproterenol 0.01 mcg/kg IP, a b adrenergic receptor agonist, to evaluate cardiac contractile reserve. Results. Plasma from CTRL patients, HF-LCRP, and HF-HCRP had no effect on resting LV fractional shortening (LVFS), while plasma from ADHF patients induced a 22.4% reduction in LVFS in healthy mice (P < 0.001 vs baseline). This reduction in LVFS was completely reversed, however, by anakinra pre-treatment. Isoproterenol induced a 46% and 43% increase in LVFS after injection with plasma from CTRL patients or HF-LCRP patients, but this isoproterenol response was significantly blunted in mice treated plasma from patients with ADHF (12.4%, P=0.005 vs CTRL) or HF-HCRP (18.2%, P=0.004 vs CTRL). The blunted response to isoproterenol was restored by pre-treatment with anakinra in mice treated with plasma from patients with ADHF (50.6%, P=0.011 vs ADHF [without anakinra pre-treatment]) and HF-HCRP (48.2%, P=0.017 vs HF-HCRP [without anakinra pre-treatment]), indicating a protective effect of IL-1 blockade. Conclusions. We report that the plasma of human HF patients with elevated inflammatory activity is sufficient to induce a cardiac dysfunction in healthy mice that is fully preventable with IL-1 blockade.
Inflammasomes are intracellular multiprotein complexes that mediate activation of caspases-1 leading to the cleavage as well as secretion of pro-inflammatory interleukin-1b (IL-1b) and that induce pyroptotic cell death. Colchicine, known as an antiinflammatory drug, binds to b-tublin and causes microtubule depolymerization and a major drug for Behçet’s disease (BD). Recently, the inhibitory effect of colchicine on stimulation-dependent caspases-1 activation has been suggested as its anti-inflammatory mechanism of colchicine, the issue has not been fully investigated. Herein we demonstrated that colchicine inhibited the caspases-1 activation in human peripheral blood mononuclear cells induced by stimulation of ATP or dsDNA, but did not inhibit the secretion of IL-1b or the pyroptotic cell death. These results imply that the repression of caspases-1 activation by colchicine may not account for its antiinflammatory effect in BD.
doi:10.1016/j.cyto.2011.07.209
PS2-050 The use of human recombinant interferon alpha 2b for the treatment of influenza caused by the pandemic influenza virus A /H1N1/ in pregnant women R.Z. Gatich, V.V. Parfenov, I.V. Polesko, V.V. Malinovskaya, G.S. Bragina, FERON Ltd. Gamaleya Reseach Institute of Epidemiology and Microbiology of the Ministry of Health and Social Development Having regard to high prevalence of influenza A/H1N1/California virus in the population, we have performed a retrospective-prospective study of the clinical course of influenza and outcomes of pregnancy in women hospitalized for influenza during the epidemiological season 2009/2010. The retrospective study was conducted in 10 toplevel clinical centers of Russia. We analyzed the case histories of 632 pregnant women hospitalized at various stages of gestation with the diagnosis of influenza A /H1N1/. 143 patients (22.6%) received symptomatic therapy, and antiviral therapy was administered to 489 patients (77.4%). Of these, 50.1% received VIFERON (rectal suppositories containing 500000 IU of human recombinant interferon alpha 2b, ascorbic acid, and tocopheryl acetate); 35.4% received Tamiflu (oseltamivir); and 8% received both drugs. Mean age of patients was 25.36 ± 0.18 years; 93.5% patients had a moderate form of the disease, and 5.7% patients had severe influenza. By the stage of gestation, the patients were distributed as follows: I trimester, 20.2%; II trimester, 40.9%; and III trimester, 38.9%. Hospitalization of the majority of patients within the first day of illness was caused by the increasing respiratory insufficiency and pregnancy-related problems, especially in patients at early stages of pregnancy. Complicated course of influenza was observed in 30.7% patients; 39.7% of them had pneumonia, and 53.6% bronchitis. Increased risk of miscarriage was observed in 41.7% at their early gestation stages. Early administration of antiviral therapy prevented from the development of complications. Comparison of the efficacy of these two drugs demonstrated that VIFERON was not inferior to Tamiflu. Administration of VIFERON starting from the first day of symptomatic illness favorably affected the clinical course of the disease, reducing the risk of complications due to viral or bacterial infections by 20%. Moreover, it was associated with a 15% lower rate of pregnancy loss as compared to patients receiving only symptomatic therapy, and this was due not only to the antiviral activity of VIFERON, but also to its immunomodulating effects expressed in the significant recovery of altered baseline characteristics of interferon status and T-cell mediated immunity. doi:10.1016/j.cyto.2011.07.210
doi:10.1016/j.cyto.2011.07.211
PS2-052 Interleukin-17 A Suppresses Eosinopoiesis By An Inducible No Synthase- And CD95L-Dependent Mechanism Pedro Xavier-Elsas, Túlio Queto, Bianca F. de Luca, Bruno Marques Vieira, Fernando Q. Cunha, Maria Ignez C Gaspar-Elsas, Department of Immunology, IMPPG, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil, Department of Pediatrics, IFF, FIOCRUZ, Rio de Janeiro, Brazil, Department of Pharmacology, Faculdade de Medicina de Ribeira& #732;o Preto-Universidade de S& #227;o Paulo, Ribeir& #227;o Preto, Brazil Interleukin-17A is a proinflammatory cytokine that plays multiple roles in autoimmune disease, neutrophil homeostasis, and allergic reactions. Eosinophils, which are prominent in allergic inflammatory infiltrates, are closely related to neutrophils, and their common progenitor might provide a target for cytokines that coordinately regulate both lineages in the bone-marrow, such as GM-CSF and G-CSF. We have recently described a pathway for suppressing bone-marrow eosinopoiesis, both in vitro and in vivo, which begins by activation of surface receptors (prostanoid or adrenergic) in committed eosinophil precursors, signals through cAMP-dependent protein kinase to induce NO synthase, and through NO to activate the proapoptotic cell surface receptor/counterreceptor pair, CD95/CD95L, ultimately inducing terminal caspase activaty. Blockade of this iNOS-CD95L-dependent pathway by the proallergic cytokines, Interleukin-13 and eotaxin, and by the cysteinyl-leukotrienes, major mediators of allergy and asthma, partly accounts for the eosinopoiesis-enhancing activity of these agonists. Here we have examined whether IL-17A suppresses eosinopoiesis, and the contribution of the iNOS-CD95L pathway to its activity in murine bone-marrow culture. IL-17A dose- and time-dependently suppressed IL-5-dependent eosinopoiesis in BALB/c bone-marrow cultures, by acting at an early precursor stage. This effect was blocked by terminal caspase inhibitor zVAD-fmk, and by deficiency in CD95 (lpr mutant mice). The effects of IL-17 A were dependent on iNOS at lower (1 ng/mL) but not higher (10 ng/mL) concentration, as shown by gene inactivation and pharmacological blockade experiments. IL-17 A, 1 ng/mL synergized with NO donor sodium nitroprusside in suppressing eosinopoiesis in iNOS-deficient bone-marrow, showing that both iNOS-dependent and –independent mechanisms are involved. Eotaxin and Leukotriene D4 blocked the effect of IL-17A. The effects of IL-17 A, a mediator of innate immunity, were enhanced in bone-marrow lacking signaling through the prototypical Th1 and Th2 cytokines, IFN- c and IL-4. These findings document a novel, regulatory effect of IL-17A on eosinophil production and add another important mediator of immunopathology to the list of substances that act on bonemarrow through the Inos-CD95L pathway. doi:10.1016/j.cyto.2011.07.212
PS2-053 Interleukin 27 ameliorates atherosclerosis by inhibiting bone marrow-derived macrophage activation in arterial walls in mice Hiroki Yoshida, Tetsuaki Hirase, Hiromitsu Hara, Yoshiyuki Miyazaki, Noriko IdeIwata, Ai Nishimoto-Hazuku, Hirokazu Fujimoto, Hiroki Yoshida, Koichi Node, Department of Biomolecular Sciences, Saga University Faculty of Medicine, Saga, Japan, Department of Cardiovascular and Renal Medicine, Saga University Faculty of Medicine, Saga, Japan, Department of Bioscience, National Cardiovascular Center Research Institute, Suita, Japan Inflammation driven by immune cells and pro-inflammatory cytokines plays a pivotal role in the development of atherosclerosis. Interleukin 27 (IL-27) is a cytokine consisting of IL27p28 and EBI3 and has anti-inflammatory properties that regulate T
Abstract / Cytokine 56 (2011) 71–77
PS2-049 Enhanced plasma Interleukin-1 activity contributes to cardiac dysfunction in heart failure Benjamin Van Tassell, Stefano Toldo, Eleonora Mezzaroma, Norbert Voelkel, Antonio Abbate, Virginia Commonwealth University
PS2-051 Colchicine inhibits the activation of inflammasomes-mediated caspases-1, but not the IL-1b production Min-yeong Woo, Okki Cho, Mi Jin Lee, Eun-So Lee, Sun Park, Dept. of Microbiology, Ajou University School of Medicine, Suwon, Korea
Background. Heart failure (HF) is a complex clinical syndrome characterized by impaired cardiac function and poor exercise tolerance. Enhanced inflammation is associated with worsening outcomes in HF patients and may play a direct role in disease progression. Interleukin-1 (IL-1) is a pro-inflammatory cytokine that becomes chronically elevated in HF and exerts putative negative inotropic effects. We hypothesized that the IL-1 activity in the plasma from HF patients would be sufficient to reproduce a phenotype of cardiac dysfunction in healthy mice. Methods. We collected blood from four groups of patients based upon HF symptoms and high sensitivity C-reactive protein (hsCRP, a surrogate marker of IL-1 activity): healthy controls (CTRL), ambulatory HF patients with low CRP (HF L-CRP), ambulatory HF with high CRP (HF H-CRP), and patients hospitalized for acute decompensated HF (ADHF). Plasma samples from each group were injected into healthy mice with transthoracic echocardiography to measure left ventricular (LV) function at baseline and 4 hours. Upon completion of echocardiography at 4 hours, all groups of mice received an injection of isoproterenol 0.01 mcg/kg IP, a b adrenergic receptor agonist, to evaluate cardiac contractile reserve. Results. Plasma from CTRL patients, HF-LCRP, and HF-HCRP had no effect on resting LV fractional shortening (LVFS), while plasma from ADHF patients induced a 22.4% reduction in LVFS in healthy mice (P < 0.001 vs baseline). This reduction in LVFS was completely reversed, however, by anakinra pre-treatment. Isoproterenol induced a 46% and 43% increase in LVFS after injection with plasma from CTRL patients or HF-LCRP patients, but this isoproterenol response was significantly blunted in mice treated plasma from patients with ADHF (12.4%, P=0.005 vs CTRL) or HF-HCRP (18.2%, P=0.004 vs CTRL). The blunted response to isoproterenol was restored by pre-treatment with anakinra in mice treated with plasma from patients with ADHF (50.6%, P=0.011 vs ADHF [without anakinra pre-treatment]) and HF-HCRP (48.2%, P=0.017 vs HF-HCRP [without anakinra pre-treatment]), indicating a protective effect of IL-1 blockade. Conclusions. We report that the plasma of human HF patients with elevated inflammatory activity is sufficient to induce a cardiac dysfunction in healthy mice that is fully preventable with IL-1 blockade.
Inflammasomes are intracellular multiprotein complexes that mediate activation of caspases-1 leading to the cleavage as well as secretion of pro-inflammatory interleukin-1b (IL-1b) and that induce pyroptotic cell death. Colchicine, known as an antiinflammatory drug, binds to b-tublin and causes microtubule depolymerization and a major drug for Behçet’s disease (BD). Recently, the inhibitory effect of colchicine on stimulation-dependent caspases-1 activation has been suggested as its anti-inflammatory mechanism of colchicine, the issue has not been fully investigated. Herein we demonstrated that colchicine inhibited the caspases-1 activation in human peripheral blood mononuclear cells induced by stimulation of ATP or dsDNA, but did not inhibit the secretion of IL-1b or the pyroptotic cell death. These results imply that the repression of caspases-1 activation by colchicine may not account for its antiinflammatory effect in BD.
doi:10.1016/j.cyto.2011.07.209
PS2-050 The use of human recombinant interferon alpha 2b for the treatment of influenza caused by the pandemic influenza virus A /H1N1/ in pregnant women R.Z. Gatich, V.V. Parfenov, I.V. Polesko, V.V. Malinovskaya, G.S. Bragina, FERON Ltd. Gamaleya Reseach Institute of Epidemiology and Microbiology of the Ministry of Health and Social Development Having regard to high prevalence of influenza A/H1N1/California virus in the population, we have performed a retrospective-prospective study of the clinical course of influenza and outcomes of pregnancy in women hospitalized for influenza during the epidemiological season 2009/2010. The retrospective study was conducted in 10 toplevel clinical centers of Russia. We analyzed the case histories of 632 pregnant women hospitalized at various stages of gestation with the diagnosis of influenza A /H1N1/. 143 patients (22.6%) received symptomatic therapy, and antiviral therapy was administered to 489 patients (77.4%). Of these, 50.1% received VIFERON (rectal suppositories containing 500000 IU of human recombinant interferon alpha 2b, ascorbic acid, and tocopheryl acetate); 35.4% received Tamiflu (oseltamivir); and 8% received both drugs. Mean age of patients was 25.36 ± 0.18 years; 93.5% patients had a moderate form of the disease, and 5.7% patients had severe influenza. By the stage of gestation, the patients were distributed as follows: I trimester, 20.2%; II trimester, 40.9%; and III trimester, 38.9%. Hospitalization of the majority of patients within the first day of illness was caused by the increasing respiratory insufficiency and pregnancy-related problems, especially in patients at early stages of pregnancy. Complicated course of influenza was observed in 30.7% patients; 39.7% of them had pneumonia, and 53.6% bronchitis. Increased risk of miscarriage was observed in 41.7% at their early gestation stages. Early administration of antiviral therapy prevented from the development of complications. Comparison of the efficacy of these two drugs demonstrated that VIFERON was not inferior to Tamiflu. Administration of VIFERON starting from the first day of symptomatic illness favorably affected the clinical course of the disease, reducing the risk of complications due to viral or bacterial infections by 20%. Moreover, it was associated with a 15% lower rate of pregnancy loss as compared to patients receiving only symptomatic therapy, and this was due not only to the antiviral activity of VIFERON, but also to its immunomodulating effects expressed in the significant recovery of altered baseline characteristics of interferon status and T-cell mediated immunity. doi:10.1016/j.cyto.2011.07.210
doi:10.1016/j.cyto.2011.07.211
PS2-052 Interleukin-17 A Suppresses Eosinopoiesis By An Inducible No Synthase- And CD95L-Dependent Mechanism Pedro Xavier-Elsas, Túlio Queto, Bianca F. de Luca, Bruno Marques Vieira, Fernando Q. Cunha, Maria Ignez C Gaspar-Elsas, Department of Immunology, IMPPG, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil, Department of Pediatrics, IFF, FIOCRUZ, Rio de Janeiro, Brazil, Department of Pharmacology, Faculdade de Medicina de Ribeira& #732;o Preto-Universidade de S& #227;o Paulo, Ribeir& #227;o Preto, Brazil Interleukin-17A is a proinflammatory cytokine that plays multiple roles in autoimmune disease, neutrophil homeostasis, and allergic reactions. Eosinophils, which are prominent in allergic inflammatory infiltrates, are closely related to neutrophils, and their common progenitor might provide a target for cytokines that coordinately regulate both lineages in the bone-marrow, such as GM-CSF and G-CSF. We have recently described a pathway for suppressing bone-marrow eosinopoiesis, both in vitro and in vivo, which begins by activation of surface receptors (prostanoid or adrenergic) in committed eosinophil precursors, signals through cAMP-dependent protein kinase to induce NO synthase, and through NO to activate the proapoptotic cell surface receptor/counterreceptor pair, CD95/CD95L, ultimately inducing terminal caspase activaty. Blockade of this iNOS-CD95L-dependent pathway by the proallergic cytokines, Interleukin-13 and eotaxin, and by the cysteinyl-leukotrienes, major mediators of allergy and asthma, partly accounts for the eosinopoiesis-enhancing activity of these agonists. Here we have examined whether IL-17A suppresses eosinopoiesis, and the contribution of the iNOS-CD95L pathway to its activity in murine bone-marrow culture. IL-17A dose- and time-dependently suppressed IL-5-dependent eosinopoiesis in BALB/c bone-marrow cultures, by acting at an early precursor stage. This effect was blocked by terminal caspase inhibitor zVAD-fmk, and by deficiency in CD95 (lpr mutant mice). The effects of IL-17 A were dependent on iNOS at lower (1 ng/mL) but not higher (10 ng/mL) concentration, as shown by gene inactivation and pharmacological blockade experiments. IL-17 A, 1 ng/mL synergized with NO donor sodium nitroprusside in suppressing eosinopoiesis in iNOS-deficient bone-marrow, showing that both iNOS-dependent and –independent mechanisms are involved. Eotaxin and Leukotriene D4 blocked the effect of IL-17A. The effects of IL-17 A, a mediator of innate immunity, were enhanced in bone-marrow lacking signaling through the prototypical Th1 and Th2 cytokines, IFN- c and IL-4. These findings document a novel, regulatory effect of IL-17A on eosinophil production and add another important mediator of immunopathology to the list of substances that act on bonemarrow through the Inos-CD95L pathway. doi:10.1016/j.cyto.2011.07.212
PS2-053 Interleukin 27 ameliorates atherosclerosis by inhibiting bone marrow-derived macrophage activation in arterial walls in mice Hiroki Yoshida, Tetsuaki Hirase, Hiromitsu Hara, Yoshiyuki Miyazaki, Noriko IdeIwata, Ai Nishimoto-Hazuku, Hirokazu Fujimoto, Hiroki Yoshida, Koichi Node, Department of Biomolecular Sciences, Saga University Faculty of Medicine, Saga, Japan, Department of Cardiovascular and Renal Medicine, Saga University Faculty of Medicine, Saga, Japan, Department of Bioscience, National Cardiovascular Center Research Institute, Suita, Japan Inflammation driven by immune cells and pro-inflammatory cytokines plays a pivotal role in the development of atherosclerosis. Interleukin 27 (IL-27) is a cytokine consisting of IL27p28 and EBI3 and has anti-inflammatory properties that regulate T