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Eosinophil Survival and Activation Sulfonylureas Inhibit Cytokine Sulfonylureas Inhibit Cytokine-Induced Eosinophil Survival and Activation Jennifer L. Bankers-Fulbright, Gail M. Kephart, David A. Loegering, Annabel L. Bradford, Shinji Okada, Hirohito Kita and This information is current as Gerald J. Gleich of September 26, 2021. J Immunol 1998; 160:5546-5553; ; http://www.jimmunol.org/content/160/11/5546 Downloaded from References This article cites 46 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/160/11/5546.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 26, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Sulfonylureas Inhibit Cytokine-Induced Eosinophil Survival and Activation1 Jennifer L. Bankers-Fulbright, Gail M. Kephart, David A. Loegering, Annabel L. Bradford, Shinji Okada, Hirohito Kita, and Gerald J. Gleich2 Eosinophils play a key role in the pathogenesis of asthma and other allergic inflammatory diseases. We have previously shown that treatment of eosinophils with lidocaine preferentially inhibits IL-5-induced survival. This inhibition cannot be overcome by increasing concentrations of IL-5 and is not due to the blocking of Na1 channels by lidocaine. Here we report that one class of K1 channel blockers, the sulfonylureas, inhibits eosinophil survival in a manner similar to lidocaine. The sulfonylurea glyburide inhibits eosinophil survival even at high concentrations of IL-5. In contrast, increasing concentrations of IL-3 or granulocyte- macrophage CSF overcome glyburide inhibition. Glyburide also blocks cytokine-induced eosinophil superoxide production. Sim- Downloaded from ilar results were seen with the sulfonylureas tolbutamide and glipizide. Interestingly, the effects of glyburide are not antagonized by the ATP-sensitive K1 channel openers cromakalim, pinacidil, or diazoxide. Although Scatchard analysis of [3H]glyburide binding to eosinophil membranes indicated that the high affinity sulfonylurea receptor (SUR1) is not present on eosinophils, human eosinophils do express mRNA homologous to the sulfonylurea receptor family, in keeping with the presence of a sulfo- nylurea receptor. Finally, coculture of eosinophils with combinations of glyburide, lidocaine, and dexamethasone resulted in synergistic inhibition of cytokine-mediated eosinophil survival and superoxide production. These results have intriguing clinical http://www.jimmunol.org/ implications for the treatment of eosinophil-associated diseases. The Journal of Immunology, 1998, 160: 5546–5553. uman asthma is characterized by reversible bronchial eosinophil granule proteins into sensitive tissues, such as the lung hyperreactivity and infiltration of inflammatory cells, es- (7–11). If, however, cytokines are present (as they are in bronchial H pecially eosinophils, into the lung (1, 2). In recent years lavage fluid from patients with asthma (12)) eosinophil survival is it has become obvious that treating the underlying inflammation is prolonged, granule proteins are released (13), and eosinophil critical to maintaining good airway function (3). The most potent apoptosis is substantially delayed (12). We reported previously agents currently used for controlling inflammation are the glu- that lidocaine treatment of eosinophils in vitro ablates cytokine- cocorticoids. However, the adverse effects of long term treatment induced survival in a manner similar to dexamethasone (14–16). by guest on September 26, 2021 with oral glucocorticoids have stimulated efforts to identify effec- Other topical anesthetics tested blocked eosinophil survival as tive anti-inflammatory substitutes (4, 5). We have previously re- well, but their potencies in the survival assay did not correlate with ported the clinical efficacy of the topical anesthetic lidocaine in the their potencies as anesthetics (17). Additionally, Na1 channel treatment of asthma in an open label trial (6). Treatment of glu- blockers that should mimic the anesthetic effect of lidocaine had no cocorticoid-dependent patients with nebulized lidocaine allowed effect on cytokine-stimulated eosinophil survival in vitro (17, 18). for the complete elimination of steroid treatment in 13 of 20 pa- These results support the hypothesis that the effect of lidocaine on tients, although exacerbations still required oral steroids. This eosinophil survival is a novel function of the drug. study suggests that lidocaine functions as an anti-inflammatory Several reports in the literature indicate that lidocaine at high agent and is thus able to replace long term oral steroid treatment. concentrations blocks K1 channels (19–21). Using three classes of Lidocaine, like the glucocorticoids, may partially exert anti- K1 channel blockers, we investigated the effect of K1 channel inflammatory effects by directly inhibiting eosinophil survival and regulation on eosinophil survival. Here we report that the sulfo- activation in the lung. In the absence of exogenous cytokines, such nylureas, one class of K1 channel blockers, inhibit eosinophil sur- as IL-5, IL-3, or GM-CSF,3 eosinophils undergo apoptosis (7–9). vival and activation in vitro. This mode of cell death with consequent engulfment by macro- phages appears to be critical for preventing the release of toxic Materials and Methods Materials HIT T15 cells were obtained from American Type Culture Collection Department of Immunology, Mayo Clinic and Mayo Foundation, Rochester, MN (Rockville, MD). Human rIL-5 was a gift from Schering Plough (Ken- 55905 ilworth, NJ). IL-3 and GM-CSF were purchased from R&D Systems (Min- Received for publication August 22, 1997. Accepted for publication January 29, 1998. neapolis, MN). Tolbutamide, glipizide, apamin, tetraethylammonium chlo- The costs of publication of this article were defrayed in part by the payment of page ride (TEA), diazoxide, and pinacidil were purchased from Research charges. This article must therefore be hereby marked advertisement in accordance Biochemicals International (Natick, MA). Unless otherwise indicated, all with 18 U.S.C. Section 1734 solely to indicate this fact. other materials were purchased from Sigma (St. Louis, MO). 1 This work was supported in part by National Institutes of Health Grants AI07047, AI34486, and AI34577 and by the Mayo Foundation. Eosinophil purification 2 Address correspondence and reprint requests to Dr. Gerald J. Gleich, Department of Eosinophils were purified from normal human subjects and patients, usu- Immunology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905. ally allergic, with slightly elevated numbers of eosinophils using a mag- 3 Abbreviations used in this paper: GM-CSF, granulocyte-macrophage CSF; TEA, netic bead separation protocol previously described (22, 23). Briefly, blood tetraethylammonium chloride; PI, propidium iodide; SUR, sulfonylurea receptor; was layered on Percoll (density 5 1.085 g/ml) and centrifuged at 900 3 g RPA, ribonuclease protection assay. to remove PBMC and hypodense (activated) eosinophils. Erythrocytes Copyright © 1998 by The American Association of Immunologists 0022-1767/98/$02.00 The Journal of Immunology 5547 were lysed by osmotic shock, and neutrophils were removed from the tated, resuspended in loading buffer, and separated on a 10% polyacryl- eosinophils by separation using a steel wool column (type CS) and anti- amide gel. The gel was transferred to a positively charged membrane (Am- CD16-conjugated magnetic beads (Miltenyi Biotec, Auburn, CA). Eosin- bion), and hybridized biotinylated probe was detected using the BrightStar ophil purity exceeded 95% as determined by Randolph’s stain. The primary BioDetect Kit (Ambion) and Kodak autoradiographic film (Eastman contaminating cells were neutrophils. Kodak, Rochester, NY). Survival assays Purified eosinophils were washed with HybriCare medium (American Statistical analysis Type Culture Collection) supplemented with 2 mM glutamine, 50 mg/ml gentamicin sulfate, and 2.5 to 10% a calf serum (HyClone, Logan, UT). Statistical analyses were performed using two-tailed, paired Student’s t Eosinophils were resuspended at 0.5 3 106 cells/ml in supplemented Hy- test. Statistical analysis of dose-dependent glyburide apoptosis induction briCare and were incubated with drugs and cytokines in 96-well plates (data not shown) was calculated using the Spearman rank correlation co- (Costar, Cambridge, MA) as indicated in the text. Drugs that were not efficient. directly soluble in media were first dissolved in DMSO and diluted to the appropriate concentrations in media. Unless indicated, the final DMSO concentration in the well never exceeded 0.5%, which was shown in con- Results trol experiments to have no effect on eosinophil survival. The final con- 1 centration of eosinophils was 5 3 104/well in a total volume of 200 ml. Effects of K channel blockers
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