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* Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
Department of Medicine, Division of Hematology-Oncology, Case Western Reserve University, Cleveland, OH 44106;
Department of Biochemistry, Virginia Commonwealth University, Richmond, VA 23298; and
Department of Molecular Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan
The mast cell (MC) inflammatory response is now linked not only to atopy, but also to arthritis, multiple sclerosis, heart disease, and resistance to bacterial infection. In the current study, we demonstrate that the signal transducer and activator of transcription 5 (Stat5) is rapidly activated by IgE cross-linkage, and that its expression is critical to the MC response. Stat5-deficient (Stat5KO) MC demonstrated a significant decrease in IgE-mediated degranulation, leukotriene B4 production, cytokine secretion, and survival signals. The defect in cytokine production may be caused by decreased cytokine mRNA stability. Stat5KO MC-induced cytokine mRNAs normally following IgE cross-linkage, but these mRNAs were not sustained over time and were degraded at twice the rate observed in WT cells. Interestingly, the RNA destabilizing protein tristetraprolin was induced following IgE cross-linkage in Stat5KO but not wild-type cells. Moreover, reducing tristetraprolin expression via short hairpin RNA transfection significantly increased IL-13 production in Stat5KO MC. Our work demonstrates that Stat5 is a critical factor in IgE-induced MC activation, acting in part via posttranscriptional control of cytokine mRNA stability. These data have a direct impact on MC-associated inflammatory and autoimmune diseases.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part National Institutes of Health Grants 1R01AI43433 and 1R01CA91839 (to the Ryan laboratory) R01DK059380 (to the Bunting laboratory).
2 Address correspondence and reprint requests to Dr. John J. Ryan, Biology Department, Virginia Commonwealth University, Box 842012, Richmond, VA 23284-2012. E-mail address: jjryan{at}saturn.vcu.edu
3 Abbreviations used in this paper: MC, mast cell; BMMC, bone marrow-derived MC; SCF, stem cell factor; Stat5, signal transducer and activator of transcription 5; Stat5KO, Stat5 deficient; shRNA, short hairpin RNA; TTP, tristetraprolin; WT, wild type; BFA, brefeldin A; LT, leukotriene; Bcl-2Tg, Bcl-2 transgenic; ActD, actinomycin D; cRPMI, complete RPMI.
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