Medeiros Monica M, Peixoto Jaqueline R, Oliveira Ana-Carolina, Cardilo-Reis Larissa, Koatz Vera L G, Van Kaer Luc, Previato José O, Mendonça-Previato Lúcia, Nobrega Alberto, Bellio Maria
Instituto de Microbiologia Prof. Paulo de Góes, Universidade Federal do Rio de Janeiro, CCS Bloco I, 20 andar Sala: I2-051, Avenida Carlos Chagas Filho, 373, Cidade Universitária, Ilha do Fundão, CEP: 21941-902, Rio de Janeiro, RJ, Brazil.
J Leukoc Biol. 2007 Sep;82(3):488-96. doi: 10.1189/jlb.0706478. Epub 2007 May 31.
We have demonstrated recently that the glycoinositolphospholipid (GIPL) molecule from the protozoan Trypanosoma cruzi is a TLR4 agonist with proinflammatory effects. Here, we show that GIPL-induced neutrophil recruitment into the peritoneal cavity is mediated by at least two pathways: one, where IL-1beta acts downstream of TNF-alpha, and a second, which is IL-1beta- and TNFRI-independent. Moreover, NKT cells participate in this proinflammatory cascade, as in GIPL-treated CD1d(-/-) mice, TNF-alpha and MIP-2 levels are reduced significantly. As a consequence of this inflammatory response, spleen and lymph nodes of GIPL-treated mice have an increase in the percentage of T and B cells expressing the CD69 activation marker. Cell-transfer experiments demonstrate that T and B cell activation by GIPL is an indirect effect, which relies on the expression of TLR4 by other cell types. Moreover, although signaling through TNFRI contributes to the activation of B and gammadelta+ T cells, it is not required for increasing CD69 expression on alphabeta+ T lymphocytes. It is interesting that T cells are also functionally affected by GIPL treatment, as spleen cells from GIPL-injected mice show enhanced production of IL-4 following in vitro stimulation by anti-CD3. Together, these results contribute to the understanding of the inflammatory properties of the GIPL molecule, pointing to its potential role as a parasite-derived modulator of the immune response during T. cruzi infection.
我们最近已证明，原生动物克氏锥虫的糖基磷脂酰肌醇（GIPL）分子是一种具有促炎作用的Toll样受体4（TLR4）激动剂。在此，我们表明，GIPL诱导的中性粒细胞募集到腹腔是由至少两条途径介导的：一条途径中，白细胞介素-1β（IL-1β）在肿瘤坏死因子-α（TNF-α）下游起作用；另一条途径则不依赖IL-1β和肿瘤坏死因子受体I（TNFRI）。此外，自然杀伤T（NKT）细胞参与了这一促炎级联反应，因为在经GIPL处理的CD1d基因敲除（CD1d(-/-)）小鼠中，TNF-α和巨噬细胞炎性蛋白-2（MIP-2）水平显著降低。作为这种炎症反应的结果，经GIPL处理的小鼠的脾脏和淋巴结中，表达CD69活化标志物的T细胞和B细胞百分比增加。细胞转移实验表明，GIPL对T细胞和B细胞的激活是一种间接效应，这依赖于其他细胞类型对TLR4的表达。此外，虽然通过TNFRI的信号传导有助于B细胞和γδ+T细胞的激活，但对于增加αβ+T淋巴细胞上CD69的表达并非必需。有趣的是，T细胞在功能上也受到GIPL处理的影响，因为来自注射GIPL的小鼠的脾细胞在抗CD3体外刺激后显示出白细胞介素-4（IL-4）产生增强。总之，这些结果有助于理解GIPL分子的炎症特性，表明其在克氏锥虫感染期间作为寄生虫衍生的免疫反应调节剂的潜在作用。
