Stamm L M, Satoskar A A, Ghosh S K, David J R, Satoskar A R
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, USA.
Eur J Immunol. 1999 Aug;29(8):2524-9. doi: 10.1002/(SICI)1521-4141(199908)29:08<2524::AID-IMMU2524>3.0.CO;2-H.
Recent studies have demonstrated that two IL-12 signaling pathways, a STAT 4 - dependent and STAT4 - independent, are involved in the development of a Th1-like response. To determine their roles in the development of protective immunity against Leishmania major, we monitored progression of cutaneous Leishmania major infection in STAT4-deficient mice (STAT4-/-) compared to similarly infected wild-type (STAT4+/+) mice. Although the onset of lesion growth was delayed in STAT4-/- mice during the early phase of infection, these mice eventually developed large, non-healing lesions, whereas STAT4+/+ mice resolved their lesions. As infection progressed, both STAT4+/+ and STAT4-/- mice infected with L. major displayed similar titers of Leishmania-specific IgG1 and IgE but later produced lower IgG2a. On days 20 and 40 post-infection, Leishmania antigen-stimulated lymphnode cells from STAT4-/- mice produced significantly lower amounts of IFN-gamma than those from STAT4+/+ mice as measured by enzyme-linked immunosorbent assay. There was no significant difference, however, in IL-4 and IL-12 production between the two groups. These results indicate that STAT4-mediated IL-12 signaling is critical for the development of protective Th1 response following L. major infection in genetically resistant mice. Additionally, they demonstrate that, although genetically resistant mice lacking STAT4 signaling pathway develop large, non-healing lesions, they do not default towards a Th2-like response.
最近的研究表明，白细胞介素-12（IL-12）的两条信号通路，即依赖信号转导和转录激活因子4（STAT4）的通路和不依赖STAT4的通路，参与了Th1样反应的发展。为了确定它们在针对硕大利什曼原虫的保护性免疫发展中的作用，我们监测了STAT4基因缺陷小鼠（STAT4-/-）与同样感染的野生型小鼠（STAT4+/+）相比，皮肤利什曼原虫主要感染的进展情况。虽然在感染早期，STAT4-/-小鼠病变生长的起始有所延迟，但这些小鼠最终发展为大的、不愈合的病变，而STAT4+/+小鼠的病变则得以消退。随着感染的进展，感染硕大利什曼原虫的STAT4+/+和STAT4-/-小鼠显示出相似的利什曼原虫特异性IgG1和IgE滴度，但随后产生的IgG2a较低。在感染后第20天和第40天，通过酶联免疫吸附测定法测量，来自STAT4-/-小鼠的利什曼原虫抗原刺激的淋巴结细胞产生的γ干扰素量明显低于来自STAT4+/+小鼠的细胞。然而，两组之间白细胞介素-4（IL-4）和白细胞介素-12（IL-12）的产生没有显著差异。这些结果表明，STAT4介导的IL-12信号通路对于基因抗性小鼠在感染硕大利什曼原虫后保护性Th1反应的发展至关重要。此外，它们还表明，虽然缺乏STAT4信号通路的基因抗性小鼠会发展出大的、不愈合的病变，但它们不会转向Th2样反应。
