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Nitric Oxide Modulation of Interleukin-1Я-Evoked Intracellular

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Nitric Oxide Modulation of Interleukin-1Я-Evoked Intracellular The Journal of Neuroscience, December 15, 2000, 20(24):8980–8986 Nitric Oxide Modulation of Interleukin-1␤-Evoked Intracellular Ca2؉ Release in Human Astrocytoma U-373 MG Cells and Brain Striatal Slices Antonella Meini,1 Alberto Benocci,1 Maria Frosini,1 Gianpietro Sgaragli,1 Gianpaolo Pessina,2 Carlo Aldinucci,2 Gise` le Tchuisseu Youmbi,1 and Mitri Palmi1 1Istituto di Scienze Farmacologiche and 2Istituto di Fisiologia, Universita` di Siena, 53100 Siena, Italy Intracellular Ca 2ϩ mobilization and release into mammal CSF Ca 2ϩ release induced by 2.5 but not 10 ng/ml IL-1␤. Ruthenium plays a fundamental role in the etiogenesis of fever induced by red (50 ␮M) and, to a lesser extent, heparin (3 mg/ml) antagonized the proinflammatory cytokine interleukin-1␤ (IL-1␤) and other IL-1␤-induced Ca 2ϩ release, and both compounds administered pyrogens. The source and mechanism of IL-1␤-induced intracel- together completely abolished this response. Similar results were lular Ca 2ϩ mobilization was investigated using two experimental obtained in human astrocytoma cells in which IL-1␤ elicited a models. IL-1␤ (10 ng/ml) treatment of rat striatal slices preloaded delayed (30 min) increase in intracellular Ca 2ϩ concentration 45 2ϩ 2ϩ Ϯ with Ca elicited a delayed (30 min) and sustained increase ([Ca ]i ) (402 71.2% of baseline), which was abolished by 1 45 2ϩ (125–150%) in spontaneous Ca release that was potentiated mML-NAME. These data indicate that the NO/cGMP-signaling by L-arginine (300 ␮M) and counteracted by N-␻-nitro-L-arginine pathway is part of the intracellular mechanism transducing IL- 2ϩ methyl ester (L-NAME) (1 and 3 mM). The nitric oxide (NO) donors 1␤-evoked Ca mobilization in glial and striatal cells and that diethylamine/NO complex (sodium salt) (0.3 and 1 mM) and the ryanodine and the inositol-(1,4,5)-trisphosphate-sensitive 2ϩ spermine/NO (0.1 and 0.3 mM) mimicked the effect of IL-1␤ on Ca stores are involved. Ca 2ϩ release. IL-1␤ stimulated tissue cGMP concentration, and dibutyryl cGMP enhanced Ca 2ϩ release. The guanyl cyclase Key words: interleukin-1␤; nitric oxide; Ca 2ϩ release; human 2ϩ inhibitors 1H-[1,2,4]oxadiazole[4,3-a] quinoxalin-1-one (100 ␮M) astrocytoma cells; rat striatum; cGMP; Ca stores; fever; and 6-[phenylamino]-5,8 quinolinedione (50 ␮M) counteracted neurotoxicity ϩ Our previous work on the mechanisms underlying the fever process sible for the increased Ca 2 observed in CSF in vivo and also ϩ showed that administration of interleukin-1␤ (IL-1␤) and other provided evidence that a specific receptor mediates Ca 2 response pyrogens into the lateral ventricle of rabbits was always accompa- (Palmi et al., 1996). ϩ ϩ nied by an increase in [Ca 2 ] in the CSF. The antipyretic acetyl- The lag phase of the Ca 2 response to IL-1␤ and the kinetic ϩ salicylic acid counteracted this effect and the increase in body pattern of Ca 2 release in these experiments were reminiscent of temperature evoked by IL-1␤ (Palmi et al., 1992). The changes in those of nitric oxide (NO) production by IL-1␤ in neurons (Bredt ϩ brain [Ca 2 ] were later shown to be strictly correlated with the et al., 1991) and other cells (Inoue et al., 1993), suggesting that NO temperature gain and with the increase in prostaglandin E2 in CSF could be the intermediate messenger responsible for this effect. of these animals, whereas the antipyretic–anti-inflammatory agent Additional support for this hypothesis is provided by reports show- dexamethasone antagonized both the fever and the increase in CSF ing that NO is involved in functions and molecular mechanisms ϩ ϩ [Ca 2 ] induced by IL-1␤ (Palmi et al., 1994). The pyrogenic effect controlling Ca 2 homeostasis in many different cell systems (for of IL-1␤ was also antagonized by lipocortin 5-(204–212) peptide, a review, see Clementi, 1998) and by the observation of increased member of the annexin family that possesses the anti-inflammatory synthesis–release of nitrite and nitrate, the breakdown products of effects of glucocorticoids (Palmi et al., 1995) as well as by NO in patients with fever (Leaf et al., 1990) or septic shock (Ochoa ventricular-cisternal perfusion with EGTA-enriched artificial CSF et al., 1991). Another relevant finding is that dexamethasone in- (Palmi et al., 1994). hibits the induction of nitric oxide synthase (NOS) (Palmer et al., ϩ Together, these findings corroborated the involvement of Ca 2 1992) and antagonizes both the fever and the increase in CSF ϩ in thermoregulation (Myers and Veale, 1970; Palmi and Sgaragli, [Ca 2 ] induced by IL-1␤ (Palmi et al., 1992). 1989), establishing the role of this ion in the intracellular signaling The aim of the present study was to investigate the involvement ϩ pathways that control the pyrogenic response to IL-1␤. Additional of NO in IL-1␤-induced Ca 2 release and the source of this in- ϩ ϩ in vitro studies showed increased Ca 2 efflux from rat striatum creased Ca 2 release. Our data showed that IL-1␤, via NO pro- ϩ treated with IL-1␤ and antagonism of this effect by a specific IL-1 duction, possesses a modulatory role on cytosolic Ca 2 concentra- receptor antagonist protein. This explained the mechanism respon- tions. Because IL-1 plays a fundamental role in diverse neurological and vascular disorders, a modulation of cytosolic ϩ Ca2 concentrations by NO may be part of the intracellular sig- Received April 10, 2000; revised Sept. 18, 2000; accepted Sept. 20, 2000. naling cascade responsible for multiple functions of this cytokine in This study was supported by contributions from the Ministero dell’Universita` della Ricerca Scientifica e Tecnologica (Cofin ’99) and the Consiglio Nazionale delle mammals. Ricerche (Roma, Italy). This article is part of the work of A.M. for the degree in Chemistry and Pharmaceutical Technologies. An abstract of this work was presented MATERIALS AND METHODS at the meeting of the Italian Society of Pharmacology, May 1997 (Bari, Italy). We Chemicals. Stock solutions of human recombinant IL-1␤ (specific activity, warmly thank Prof. S. Nicosia (Institute of Pharmaceutical Sciences, University of ϫ 9 2ϩ 1.0 10 U/mg protein), which was kindly donated by Chiron Vaccines Milan, Milan, Italy) for her helpful suggestions in performing Ca experiments with S.p.A. (Siena, Italy) were prepared by dissolving the compound in double- fura-2. distilled pyrogen-free water. The solutions were divided into aliquots and Correspondence should be addressed to Dr. Mitri Palmi, Istituto di Scienze Farma- stored under nitrogen. Each solution was thawed and diluted before use. cologiche, Universita` di Siena, via Piccolomini 170, 53100 Siena, Italy. E-mail: Lipopolysaccharide contamination of IL-1␤ was Ͻ1.2 pg/␮g as measured by 45 2ϩ Ϫ6 [email protected]. the limulus amebocyte lysate chromogenic assay. Ca (6.02 ϫ 10 M) Copyright © 2000 Society for Neuroscience 0270-6474/00/208980-07$15.00/0 (specific activity, 532 mCi/mmol) was obtained from DuPont NEN (Cologno Meini et al. • Nitric Oxide Modulation of IL-1␤-Evoked Ca2ϩ Release J. Neurosci., December 15, 2000, 20(24):8980–8986 8981 ϩ Monzese, Milano, Italy). Fura-2 AM in anhydrous dimethylsulfoxide in IL-1␤-induced Ca 2 release, we tested the effect of RR, a specific (DMSO) from Calbiochem (Milano, Italy) was stored in aliquots at Ϫ80°C inhibitor of the ryanodine (RY)-sensitive receptors and heparin, which and thawed before use. 1H-[1,2,4] oxadiazole [4,3-a] quinoxalin-1-one inhibits the inositol-(1,4,5)-trisphosphate (IP3)-sensitive receptors, as well (ODQ) from Tocris Cookson (Bristol, UK) and 6[phenylamino]-5,8 quin- as the mitochondrial uniport for calcium. Tissuesϩ pretreated with saponin oline dione (LY-83,583) from Alexis Corporation (Laufelfingen, Switzerland) (1.5 mg/ml) during the 30 min of the “ 45Ca2 loading period” were then 2ϩ were dissolved in 3% DMSO. 2-(N,N-Diethylamino)-diazenolate-2-oxide perfused with a Ca -free solution in the presence of RR (50 ␮M), [sodium salt (Dea/NO)] and [(z)-1–123 N-[3-aminopropyl]-N-[4-(3-amino- heparin (3 mg/ml), or RR plus heparin. propylammonio)butyl]-amino 125-diazen-1-ium-1,2-diodate] (Sper/NO) were Nitric oxide assay. To estimate the amount of NO released by the NO from Alexis Biochemicals (Vinci, Italy). 4-Bromocalcimycin (4Br-A23187) and donors, concentrations of nitrite and nitrate after enzymatic reduction, the digitonin from Merck (Darmstadt, Germany) were dissolved in DMSO. Plu- end-products of NO, were measured by the Griess reaction by using a ronic acid F-127 was from Molecular Probes (Eugene, OR). DMEM and fetal commercial colorimetric assay kit (detection limit, 2.0 ␮M; Cayman Chem- calf serum were from Seromed (Biochrom KG, Berlin, Germany). Human ical, Ann Arbor, MI). Amounts of NO released were determined in the astrocytoma U-373 MG cells were obtained courtesy of Prof. Chieco Bianchi absence of tissue under the same experimental conditions. After addition (Institute of Oncology, Padua University, Padua, Italy). Low molecular weight of NO donors to 0.2 mM Ca-EGTA buffer, pH 7.4 (37°C), to initiate the heparin (ϳ3000 Da) and all other chemicals were from Sigma (St. Louis, MO). reaction, samples of 1.5 ml were collected through the perfusion apparatus Solutions. Physiological salt solution (PSS) contained (in mM): 160 NaCl, at 3 min intervals. The samples were collected in tubes containing 0.1 N 10 glucose, 5 HEPES, 4.6 KCl, and 1 MgCl2, pH 7.2. Ca-EGTA PSS NaOH to stop the reaction, and the samples were immediately frozen and contained (in mM): 135 NaCl, 10 D-glucose, 5 HEPES, 4.6 KCl, and 1 analyzed at the end of the experiment.
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