Heinisch I V, Bizer C, Volgger W, Simon H U
Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Switzerland.
J Allergy Clin Immunol. 2001 Jul;108(1):21-8. doi: 10.1067/mai.2001.116864.
CD137 (ILA/4-1BB), a member of the TNF/nerve growth factor receptor superfamily, has previously been suggested to be involved in T-cell activation and differentiation.
The aim of this study was to investigate expression and potential function of CD137 in eosinophils.
Eosinophils were isolated from normal control subjects as well as from patients with bronchial asthma, patients with atopic dermatitis, and patients with idiopathic eosinophilia. CD137 expression was analyzed by RT-PCR and flow cytometry. The in situ expression of CD137 on eosinophils in nasal polyp and skin tissues was analyzed through use of immunohistochemistry. To examine whether CD137 regulates eosinophil death and apoptosis, cells were stimulated with a plate-bound anti-CD137 antibody in the presence or absence of survival cytokines. Cell death was measured by means of an ethidium bromide exclusion test. Apoptosis was determined by analyzing phosphatidylserine surface exposure.
Blood and tissue eosinophils from patients with IgE-mediated allergic responses (atopic dermatitis, extrinsic asthma) express CD137. In contrast, eosinophils from normal control individuals and patients with non-IgE-mediated eosinophilic inflammatory responses (intrinsic asthma, idiopathic eosinophilia) express neither detectable levels of mRNA nor protein for CD137. Expression of CD137 in eosinophils was induced in vitro by stimulating the cells with supernatants derived from in vivo- or in vitro-activated T cells, suggesting that a soluble T cell-derived factor might be responsible for the observed phenomenon. Although CD137 expression was associated with increased IgE levels, IL-4 and IL-13 did not induce CD137 gene expression in eosinophils. Activation of CD137 abrogated both GM-CSF-mediated and IL-5-mediated antiapoptosis in CD137-expressing eosinophils but not in CD137-deficient eosinophils. In contrast, the survival effect of IFN-gamma was not affected by anti-CD137 treatment.
Our data indicate that CD137 activation might limit GM-CSF-mediated and IL-5-mediated antiapoptosis of eosinophils. The absence of this potential anti-inflammatory mechanism might further increase eosinophil numbers at inflammatory sites in patients with intrinsic asthma and patients with idiopathic eosinophilia. The T cell-derived factor that induces CD137 expression in eosinophils remains to be identified.
CD137（ILA/4-1BB）是TNF/神经生长因子受体超家族的成员，此前有研究表明其参与T细胞的激活和分化。
本研究旨在探讨CD137在嗜酸性粒细胞中的表达及潜在功能。
从正常对照者以及支气管哮喘患者、特应性皮炎患者和特发性嗜酸性粒细胞增多症患者中分离嗜酸性粒细胞。通过RT-PCR和流式细胞术分析CD137的表达。利用免疫组织化学分析鼻息肉和皮肤组织中嗜酸性粒细胞上CD137的原位表达。为检测CD137是否调节嗜酸性粒细胞的死亡和凋亡，在有或无存活细胞因子存在的情况下，用板结合抗CD137抗体刺激细胞。通过溴化乙锭排除试验检测细胞死亡情况。通过分析磷脂酰丝氨酸表面暴露情况来确定凋亡。
来自IgE介导的过敏反应（特应性皮炎、外源性哮喘）患者的血液和组织嗜酸性粒细胞表达CD137。相比之下，正常对照个体以及非IgE介导的嗜酸性粒细胞炎症反应（内源性哮喘、特发性嗜酸性粒细胞增多症）患者的嗜酸性粒细胞既未检测到CD137的mRNA水平，也未检测到蛋白质水平。用体内或体外激活的T细胞来源的上清液刺激细胞，可在体外诱导嗜酸性粒细胞中CD137的表达，这表明可溶性T细胞来源的因子可能是导致该现象的原因。虽然CD137的表达与IgE水平升高有关，但IL-4和IL-13并未诱导嗜酸性粒细胞中CD137基因的表达。CD137的激活消除了GM-CSF介导的和IL-5介导的抗凋亡作用，在表达CD137的嗜酸性粒细胞中是这样，但在缺乏CD137的嗜酸性粒细胞中则不然。相比之下，IFN-γ的存活作用不受抗CD137治疗的影响。
我们的数据表明，CD137的激活可能会限制GM-CSF介导的和IL-5介导的嗜酸性粒细胞抗凋亡作用。内源性哮喘患者和特发性嗜酸性粒细胞增多症患者炎症部位缺乏这种潜在的抗炎机制，可能会进一步增加嗜酸性粒细胞的数量。诱导嗜酸性粒细胞中CD137表达的T细胞来源因子仍有待确定。
