Barral A, Barral-Netto M, Yong E C, Brownell C E, Twardzik D R, Reed S G
Seattle Biomedical Research Institute, WA 98109.
Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3442-6. doi: 10.1073/pnas.90.8.3442.
Transforming growth factor beta (TGF-beta) has potent down-regulating effects on macrophages and is thus capable of influencing the fate of intramacrophage parasites, including leishmanias. We report the development of a mouse model for the study of the human pathogen Leishmania braziliensis and demonstrate, both in vitro and in vivo, a key regulatory role for TGF-beta in the pathogenesis of infection with this parasite. Recombinant TGF-beta added to cultures of murine peritoneal macrophages led to increased intracellular L. braziliensis replication, whereas addition of neutralizing anti-TGF-beta monoclonal antibody decreased levels of infection. Macrophages infected with L. braziliensis produced biologically active TGF-beta, with a direct correlation between amounts of TGF-beta induced by two parasite isolates and their relative virulence. In vivo, treatment with recombinant TGF-beta rendered avirulent parasites virulent and activated latent L. braziliensis infection. Activation of parasite replication was observed in mice which had been infected with L. braziliensis 15 weeks previously but had not developed lesions or had healed lesions, depending on the parasite isolate used to infect the mice. The exacerbation of L. braziliensis infection in vivo was associated with an increase of interleukin 10 mRNA in the draining lymph node. These results demonstrate that TGF-beta is able to alter the course of in vitro and in vivo infections with L. braziliensis, the latter being characterized by an increase in interleukin 10, an important Th2 helper-T-cell cytokine.
转化生长因子β（TGF-β）对巨噬细胞具有强大的下调作用，因此能够影响巨噬细胞内寄生虫的命运，包括利什曼原虫。我们报告了一种用于研究人类病原体巴西利什曼原虫的小鼠模型的建立，并在体外和体内证明了TGF-β在这种寄生虫感染发病机制中的关键调节作用。向小鼠腹腔巨噬细胞培养物中添加重组TGF-β会导致细胞内巴西利什曼原虫的复制增加，而添加中和性抗TGF-β单克隆抗体则会降低感染水平。感染巴西利什曼原虫的巨噬细胞会产生具有生物活性的TGF-β，两种寄生虫分离株诱导产生的TGF-β量与其相对毒力之间存在直接相关性。在体内，用重组TGF-β治疗可使无毒力的寄生虫具有毒力，并激活潜伏的巴西利什曼原虫感染。在15周前感染了巴西利什曼原虫但未出现病变或病变已愈合的小鼠中，观察到寄生虫复制的激活，这取决于用于感染小鼠的寄生虫分离株。体内巴西利什曼原虫感染的加剧与引流淋巴结中白细胞介素10 mRNA的增加有关。这些结果表明，TGF-β能够改变巴西利什曼原虫在体外和体内的感染进程，后者的特征是白细胞介素10增加，白细胞介素10是一种重要的Th2辅助性T细胞细胞因子。
