Thawani Neeta, Tam Mifong, Stevenson Mary M
Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, Montreal, Quebec, H3G 1A4, Canada.
Haematologica. 2009 Feb;94(2):195-204. doi: 10.3324/haematol.13422. Epub 2008 Dec 23.
BACKGROUND: The contribution of pro-inflammatory cytokines to the pathogenesis of malarial anemia has been studied extensively but the roles of Th2 cytokines remain unknown. Here, we investigated the role of signal transducer and activator of transcription (STAT)6-mediated responses in erythropoietic suppression during acute malaria infection in mice. DESIGN AND METHODS: Naïve and/or erythropoietin-treated wild-type and STAT6(-/-) mice were infected with Plasmodium chabaudi AS (P. chabaudi), and the effects parasitemia, hematologic parameters, erythropoietin receptor, TER119, and CD71 expression, in vitro erythropoietin-stimulated proliferation of splenic erythroid precursors, and serum cytokine levels were analyzed. To explore the role of interleukin-4 in STAT6-dependent erythropoietic suppression, mice were treated in vivo with a monoclonal antibody to interleukin-4 and the effects on parasitemia, hematologic parameters, and cytokine levels were analyzed. RESULTS: Infected STAT6(-/-) mice developed enhanced reticulocytosis compared to wild-type mice despite higher parasitemia and a similar course of anemia. Enhanced reticulocytosis in infected STAT6(-/-) mice was associated with an increased frequency of late-stage erythroblasts, fewer leukocytes expressing CD71, and increased erythropoietin-stimulated proliferation of splenocytes compared to infected wild-type mice. Interleukin-4-depleted wild-type mice had increased levels of parasitemia and a course of reticulocytosis similar to responses observed in infected STAT6(-/-) mice. Determination of serum cytokine levels in STAT6(-/-) and wild-type mice depleted of interleukin-4 by treatment with mAb revealed significantly lower levels of interferon-gamma compared to control wild-type mice during infection. CONCLUSIONS: Together, these findings provide evidence for a STAT6-dependent mechanism in mediating erythropoietic suppression during acute blood-stage malaria and indicate a role for interleukin-4 and possibly interferon-gammain STAT6-induced erythropoietic suppression.
背景：促炎细胞因子在疟疾贫血发病机制中的作用已得到广泛研究，但Th2细胞因子的作用仍不清楚。在此，我们研究了信号转导和转录激活因子（STAT）6介导的反应在小鼠急性疟疾感染期间红细胞生成抑制中的作用。 设计与方法：用夏氏疟原虫AS（P. chabaudi）感染未经处理和/或经促红细胞生成素处理的野生型和STAT6基因敲除（STAT6(-/-)）小鼠，并分析疟原虫血症、血液学参数、促红细胞生成素受体、TER119和CD71表达、体外促红细胞生成素刺激的脾红细胞前体增殖以及血清细胞因子水平的影响。为了探讨白细胞介素-4在STAT6依赖性红细胞生成抑制中的作用，给小鼠体内注射抗白细胞介素-4单克隆抗体，并分析其对疟原虫血症、血液学参数和细胞因子水平的影响。 结果：尽管感染的STAT6(-/-)小鼠疟原虫血症较高且贫血病程相似，但与野生型小鼠相比，其网织红细胞增多症有所增强。与感染的野生型小鼠相比，感染的STAT6(-/-)小鼠网织红细胞增多症增强与晚期成红细胞频率增加、表达CD71的白细胞减少以及脾细胞促红细胞生成素刺激的增殖增加有关。白细胞介素-4缺失的野生型小鼠疟原虫血症水平升高，网织红细胞增多症病程与感染的STAT6(-/-)小鼠中观察到的反应相似。用单克隆抗体处理使白细胞介素-4缺失的STAT6(-/-)和野生型小鼠血清细胞因子水平测定显示，感染期间干扰素-γ水平明显低于对照野生型小鼠。 结论：总之，这些发现为急性血液期疟疾期间介导红细胞生成抑制的STAT6依赖性机制提供了证据，并表明白细胞介素-4以及可能的干扰素-γ在STAT6诱导的红细胞生成抑制中起作用。
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