Am. J. Respir. Crit. Care Med., Volume 159, Number 6, June 1999, 1903-1909

Inhibition of cPLA₂ Translocation and Leukotriene C₄ Secretion by Fluticasone Propionate in Exogenously Activated Human Eosinophils

AKIKO SANO, NILDA M. MUÑOZ, HIROYUKI SANO, JOHN CHOI, XIANGDONG ZHU, BENJAMIN JACOBS, and ALAN R. LEFF

Section of Pulmonary and Critical Care Medicine, Department of Medicine, and Departments of Pharmacological and Physiological Sciences and Committees on Clinical Pharmacology and Cellular Physiology, The University of Chicago, Chicago, Illinois

We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A₂ (cPLA₂), and (2) blockade of leukotriene C₄ (LTC₄) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10¹⁰ M to 10⁶ M FP in the presence of 10 pg/ml human recombinant interleukin-5 (rhIL-5) and activated with formyl-met-leu-phe (FMLP) + cytochalasin B (CB). At 24 h, stimulated LTC₄ secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC₄ secretion decreased from 1,429 ± 327 pg/10⁶ cells to 762 ± 113 pg/10⁶ cells for eosinophils treated for 48 h with  10⁸ M FP (p < 0.003). FMLP/CB-stimulated translocation of cPLA₂ to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by FP. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10¹⁰ M FP, and inhibition of LTC₄ synthesis was reversed by exogenous arachidonic acid (AA). We find that FP causes a decrease in stimulated eosinophil secretion of LTC₄ that is regulated by phospholipase A₂ (PLA₂). Inhibition of LTC₄ synthesis precedes the global cytotoxic effects of FP as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of cPLA₂ to the nuclear envelope during cellular activation.

This article has been cited by other articles:

				A. Y. Meliton, N. M. Munoz, X. Zhu, and A. R. Leff Attenuated translocation of group IVa phospholipase A2 and up-regulated annexin-1 synthesis by glucocorticoid blocks {beta}2-integrin adhesion in neutrophils J. Leukoc. Biol., February 1, 2008; 83(2): 344 - 351. [Abstract] [Full Text] [PDF]

				A. R. Leff and N. M. Munoz Future Treatment to Lessen Exacerbations of Chronic Obstructive Pulmonary Disease Proceedings of the ATS, December 1, 2007; 4(8): 659 - 666. [Abstract] [Full Text] [PDF]

				N. Flamand, J. Lefebvre, G. Lapointe, S. Picard, L. Lemieux, S. G. Bourgoin, and P. Borgeat Inhibition of platelet-activating factor biosynthesis by adenosine and histamine in human neutrophils: involvement of cPLA2{alpha} and reversal by lyso-PAF J. Leukoc. Biol., May 1, 2006; 79(5): 1043 - 1051. [Abstract] [Full Text] [PDF]

				A.R. Leff From the Authors Eur. Respir. J., August 1, 2004; 24(2): 334 - 334. [Full Text] [PDF]

				A. Papi Investigating the steroids and long-acting {beta}2-agonists combination: why do we need more? Eur. Respir. J., April 1, 2004; 23(4): 501 - 502. [Full Text] [PDF]

				S. Myo, X. Zhu, S. Myou, A.Y. Meliton, J. Liu, E. Boetticher, A.T. Lambertino, C. Xu, N.M. Munoz, and A.R. Leff Additive blockade of {beta}2-integrin adhesion of eosinophils by salmeterol and fluticasone propionate Eur. Respir. J., April 1, 2004; 23(4): 511 - 517. [Abstract] [Full Text] [PDF]

				N. M. Munoz, Y. J. Kim, A. Y. Meliton, K. P. Kim, S.-K. Han, E. Boetticher, E. O'Leary, S. Myou, X. Zhu, J. V. Bonventre, et al. Human Group V Phospholipase A2 Induces Group IVA Phospholipase A2-independent Cysteinyl Leukotriene Synthesis in Human Eosinophils J. Biol. Chem., October 3, 2003; 278(40): 38813 - 38820. [Abstract] [Full Text] [PDF]

				T. Terashima, K. Amakawa, A. Matsumaru, and K. Yamaguchi Correlation Between Cysteinyl Leukotriene Release From Leukocytes and Clinical Response to a Leukotriene Inhibitor Chest, November 1, 2002; 122(5): 1566 - 1570. [Abstract] [Full Text] [PDF]

				N. M. Munoz, G. A. van Seventer, R. T. Semnani, and A. R. Leff Augmentation of LTC4 synthesis in human eosinophils caused by CD3-stimulated Th2-like cells in vitro Am J Physiol Lung Cell Mol Physiol, June 1, 2000; 278(6): L1172 - L1179. [Abstract] [Full Text] [PDF]

				I. S. Douglas, A. R. Leff, and A. I. Sperling CD4+ T Cell and Eosinophil Adhesion Is Mediated by Specific ICAM-3 Ligation and Results in Eosinophil Activation J. Immunol., March 15, 2000; 164(6): 3385 - 3391. [Abstract] [Full Text] [PDF]

				P. P Hood, T. P Cotter, J. F Costello, and A. P Sampson Effect of intravenous corticosteroid on ex vivo leukotriene generation by blood leucocytes of normal and asthmatic patients Thorax, December 1, 1999; 54(12): 1075 - 1082. [Abstract] [Full Text]