Proviral integration site for Moloney murine leukemia virus 1, but not phosphatidylinositol-3 kinase, is essential in the antiapoptotic signaling cascade initiated by IL-5 in eosinophils
Proviral integration site for Moloney murine leukemia virus 1, but not phosphatidylinositol-3 kinase, is essential in the antiapoptotic signaling cascade initiated by IL-5 in eosinophils
复制标题
DOI：
10.1016/j.jaci.2008.12.004
复制
发表时间：
2009-03-01
影响因子：
14.2
通讯作者：
Simon, Hans-Uwe
中科院分区：
文献类型：
--
作者：
Andina, Nicola;Didichenko, Svetlana;Simon, Hans-Uwe
背景：嗜酸性粒细胞的分化、激活和存活在很大程度上受IL-5的调节。IL-5介导的跨膜信号转导涉及Lyn丝裂原活化蛋白激酶和Janus Kins2-信号转导和转录激活子通路。目的：我们试图确定其他信号分子/通路是否在IL-5介导的嗜酸性粒细胞存活中起关键作用。方法：体外检测嗜酸性粒细胞在IL-5存在和不存在的情况下的存活和凋亡情况。用含有野生型Pim-1或显性阴性Pim-1的HIV-转录反式激活因子融合蛋白检测Moloney小鼠白血病病毒(PIM)1丝氨酸/苏氨酸激酶前整合位点的特异性作用。结果：LY294002、Wortmannin或选择性PI3K p110β异构体抑制剂IC87114均能有效抑制PI3K的表达，但仅LY294002能阻断IL-5介导的嗜酸性粒细胞存活增加。这表明除了PI3K外，LY294002还抑制了另一种与这一过程密切相关的激酶。事实上，在体外IL-5刺激后，Pim-1在嗜酸性粒细胞中迅速而强烈地表达，并在体内炎症条件下很容易在嗜酸性粒细胞中检测到。结论：在IL-5介导的嗜酸性粒细胞抗凋亡信号转导中，Pim-1起主要作用，而不是PI3K。(《过敏与免疫杂志》2009；123：603-.11.)
Background: Eosinophil differentiation, activation, and survival are largely regulated by IL-5. IL-5-mediated transmembrane signal transduction involves both Lyn-mitogen-activated protein kinases and Janus kinase 2-signal transducer and activator of transcription pathways.Objective: We sought to determine whether additional signaling molecules/pathways are critically involved in IL-5-mediated eosinophil survival.Methods: Eosinophil survival and apoptosis were measured in the presence and absence of IL-5 and defined pharmacologic inhibitors in vitro. The specific role of the serine/threonine kinase proviral integration site for Moloney murine leukemia virus (Pim) 1 was tested by using HIV-transactivator of transcription fusion proteins containing wild-type Pim-1 ora dominant-negative form of Pim-1. The expression of Pim-1 in eosinophils was analyzed by means of immunoblotting and immunofluorescence.Results: Although pharmacologic inhibition of phosphatidylinositol-3 kinase (PI3K) by LY294002, wortmannin, or the selective PI3K p110 delta isoform inhibitor IC87114 was successful in each case, only LY294002 blocked increased IL-5-mediated eosinophil survival. This suggested that LY294002 inhibited another kinase that is critically involved in this process in addition to PI3K. Indeed, Pim-1 was rapidly and strongly expressed in eosinophils after IL-5 stimulation in vitro and readily detected in eosinophils under inflammatory conditions in vivo. Moreover, by using specific protein transfer, we identified Pim-1 as a critical element in IL-5-mediated antiapoptotic signaling in eosinophils.Conclusions: Pim-1, but not PI3K, plays a major role in IL-5-mediated antiapoptotic signaling in eosinophils. (J Allergy Clin Immunol 2009;123:603-.11.)