RETRACTED: Sphingosine Kinase1 Is Pivotal for FcεRI-Mediated Mast Cell Signaling and Functional Responses In Vitro and In Vivo (Retracted Article)

被引:28
作者
Pushparaj, Peter N. [1 ]
Manikandan, Jayapal [2 ]
Tay, Hwee Kee [1 ]
H'ng, Shiau Chen [2 ]
Kumar, Srinivasan D. [3 ]
Pfeilschifter, Josef [4 ]
Huwiler, Andrea [5 ]
Melendez, Alirio J. [1 ,2 ]
机构
[1] Univ Glasgow, Glasgow Biomed Res Ctr, Glasgow, Lanark, Scotland
[2] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117595, Singapore
[3] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Anat, Singapore 117595, Singapore
[4] Univ Hosp, Pharmazentrum Frankfurt, Zentrum Arzneimittelforsch Entwicklung & Sicherhe, Frankfurt, Germany
[5] Univ Bern, Inst Pharmacol, Bern, Switzerland
基金
英国医学研究理事会;
关键词
AIRWAY SMOOTH-MUSCLE; GENE-EXPRESSION; INFLAMMATORY RESPONSES; CYTOKINE PRODUCTION; KNOCKOUT MICE; KAPPA-B; IGE; RECEPTOR; SPHINGOSINE-1-PHOSPHATE; ANAPHYLAXIS;
D O I
10.4049/jimmunol.0803430
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Mast cell degranulation is pivotal to allergic diseases; investigating novel pathways triggering mast cell degranulation would undoubtedly have important therapeutic potential. Fc epsilon RI-mediated degranulation has contradictorily been shown to require SphK1 or SphK2, depending on the reports. We investigated the in vitro and in vivo specific role(s) of SphK1 and SphK2 in Fc epsilon RI-mediated responses, using specific small interfering RNA-gene silencing. The small interfering RNA-knockdown of SphK1 in mast cells inhibited several signaling mechanisms and effector functions, triggered by Fc epsilon RI stimulation including: Ca2+ signals, NF kappa B activation, degranulation, cytokine/chemokine, and eicosanoid production, whereas silencing SphK2 had no effect at all. Moreover, silencing SPHK1 in vivo, in different strains of mice, strongly inhibited mast cell-mediated anaphylaxis, including inhibition of vascular permeability, tissue mast cell degranulation, changes in temperature, and serum histamine and cytokine levels, whereas silencing SPHK2 had no effect and the mice developed anaphylaxis. Our data differ from a recent report using SPHK1(-/-) and SPHK2(-/-) mice, which showed that SphK2 was required for FC epsilon RI-mediated mast cell responses. We performed experiments in mast cells derived from SPHK1(-/-) and SPHK2(-/-) mice and show that the calcium response and degranulation, triggered by Fc epsilon RI-cross-linking, is not different from that triggered in wild-type cells. Moreover, IgE-mediated anaphylaxis in the knockout mice showed similar levels in temperature changes and serum histamine to that from wild-tvpe mice, indicating that there was no protection from anaphylaxis for either knockout mice. Thus, our data strongly suggest a previously unrecognized compensatory mechanism in the knockout mice, and establishes a role for SphK1 in IgE-mediated mast cell responses. The Journal of Immunology, 2009, 183: 221-227.
引用
收藏
页码:221 / 227
页数:7
相关论文
共 36 条
[1]   Sphingosine 1-phosphate modulates human airway smooth muscle cell functions that promote inflammation and airway remodeling in asthma [J].
Ammit, AJ ;
Hastie, AT ;
Edsall, LC ;
Hoffman, RK ;
Amrani, Y ;
Krymskaya, VP ;
Kane, SA ;
Peters, SP ;
Penn, RB ;
Spiegel, S ;
Panettieri, RA .
FASEB JOURNAL, 2001, 15 (07) :1212-1214
[2]  
Barbaric Ivana, 2007, Briefings in Functional Genomics & Proteomics, V6, P91, DOI 10.1093/bfgp/elm008
[3]   Sphingolipids and the regulation of the immune response [J].
Baumruker, T ;
Prieschl, EE .
SEMINARS IN IMMUNOLOGY, 2002, 14 (01) :57-63
[4]   Role of mast cells in allergic and non-allergic immune responses: comparison of human and murine data [J].
Bischoff, Stephan C. .
NATURE REVIEWS IMMUNOLOGY, 2007, 7 (02) :93-104
[5]   The ins and outs of IgE-dependent mast-cell exocytosis [J].
Blank, U ;
Rivera, J .
TRENDS IN IMMUNOLOGY, 2004, 25 (05) :266-273
[6]   SPHINGOSINE-1-PHOSPHATE INHIBITS PDGF-INDUCED CHEMOTAXIS OF HUMAN ARTERIAL SMOOTH-MUSCLE CELLS - SPATIAL AND TEMPORAL-MODULATION OF PDGF CHEMOTACTIC SIGNAL-TRANSDUCTION [J].
BORNFELDT, KE ;
GRAVES, LM ;
RAINES, EW ;
IGARASHI, Y ;
WAYMAN, G ;
YAMAMURA, S ;
YATOMI, Y ;
SIDHU, JS ;
KREBS, EG ;
HAKOMORI, S ;
ROSS, R .
JOURNAL OF CELL BIOLOGY, 1995, 130 (01) :193-206
[7]   Mast-cell infiltration of airway smooth muscle in asthma [J].
Brightling, CE ;
Bradding, P ;
Symon, FA ;
Holgate, ST ;
Wardlaw, AJ ;
Pavord, ID .
NEW ENGLAND JOURNAL OF MEDICINE, 2002, 346 (22) :1699-1705
[8]  
Choi OH, 1996, NATURE, V380, P634
[9]   Calcium oscillations increase the efficiency and specificity of gene expression [J].
Dolmetsch, RE ;
Xu, KL ;
Lewis, RS .
NATURE, 1998, 392 (6679) :933-936
[10]   ABOLITION OF ANAPHYLAXIS BY TARGETED DISRUPTION OF THE HIGH-AFFINITY IMMUNOGLOBULIN-E RECEPTOR ALPHA-CHAIN GENE [J].
DOMBROWICZ, D ;
FLAMAND, V ;
BRIGMAN, KK ;
KOLLER, BH ;
KINET, JP .
CELL, 1993, 75 (05) :969-976