Rodriguez-Galán Maria Cecilia, Bream Jay H, Farr Andrew, Young Howard A
Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
J Immunol. 2005 Mar 1;174(5):2796-804. doi: 10.4049/jimmunol.174.5.2796.
In the periphery, IL-18 synergistically induces the expression of the Th1 cytokine IFN-gamma in the presence of IL-12 and the Th2 cytokines IL-5 and IL-13 in the presence of IL-2. Although the expression of these cytokines has been described in the thymus, their role in thymic development and function remains uncertain. We report here that freshly isolated thymocytes from C57BL/6 and BALB/c mice stimulated in vitro with IL-2-plus-IL-18 or IL-12-plus-IL-18 produce large amounts of IFN-gamma and IL-13. Analysis of the thymic subsets, CD4(-)CD8(-) (DN), CD4(+)CD8(+), CD4(+)CD8(-), and CD4(-)CD8(+) revealed that IL-18 in combination with IL-2 or IL-12 induces IFN-gamma and IL-13 preferentially from DN cells. Moreover, DN2 and DN3 thymocytes contained more IFN-gamma(+) cells than cells in the later stage of maturation. Additionally, IL-18 in combination with IL-2 induces CCR4 (Th2-associated) and CCR5 (Th1-associated) gene expression. In contrast, IL-18-plus-IL-12 specifically induced CCR5 expression. The IL-2-plus-IL-18 or IL-12-plus-IL-18 effect on IFN-gamma and IL-13 expression is dependent on Stat4 and NF-kappaB but independent of Stat6, T-bet, or NFAT. Furthermore, IL-12-plus-IL-18 induces significant thymocyte apoptosis when expressed in vivo or in vitro, and this effect is exacerbated in the absence of IFN-gamma. IL-12-plus-IL-18-stimulated thymocytes can also induce IA-IE expression on cortical and medullary thymic epithelial cells in an IFN-gamma-dependent manner. Thus, the combination of IL-2, IL-12, and IL-18 can induce phenotypic and functional changes in thymocytes that may alter migration, differentiation, and cell death of immature T cells inside the thymus and potentially affect the Th1/Th2 bias in peripheral immune compartments.
在外周，白细胞介素-18（IL-18）在白细胞介素-12（IL-12）存在的情况下协同诱导Th1细胞因子γ干扰素（IFN-γ）的表达，在白细胞介素-2（IL-2）存在的情况下协同诱导Th2细胞因子白细胞介素-5（IL-5）和白细胞介素-13（IL-13）的表达。尽管这些细胞因子在胸腺中的表达已有描述，但其在胸腺发育和功能中的作用仍不确定。我们在此报告，来自C57BL/6和BALB/c小鼠的新鲜分离胸腺细胞，在体外经IL-2加IL-18或IL-12加IL-18刺激后，会产生大量的IFN-γ和IL-13。对胸腺亚群CD4(-)CD8(-)（双阴性，DN）、CD4(+)CD8(+)、CD4(+)CD8(-)和CD4(-)CD8(+)的分析显示，IL-18与IL-2或IL-12联合使用时，优先从DN细胞诱导IFN-γ和IL-13的产生。此外，DN2和DN3胸腺细胞中的IFN-γ(+)细胞比成熟后期的细胞更多。另外，IL-18与IL-2联合使用可诱导CCR4（与Th2相关）和CCR5（与Th1相关）基因的表达。相反，IL-18加IL-12特异性诱导CCR5的表达。IL-2加IL-18或IL-12加IL-18对IFN-γ和IL-13表达的影响依赖于信号转导和转录激活因子4（Stat4）和核因子κB（NF-κB），但不依赖于信号转导和转录激活因子6（Stat6）、T盒转录因子（T-bet）或活化T细胞核因子（NFAT）。此外，IL-12加IL-18在体内或体外表达时会诱导显著的胸腺细胞凋亡，且在没有IFN-γ的情况下这种作用会加剧。IL-12加IL-18刺激的胸腺细胞还能以IFN-γ依赖的方式诱导皮质和髓质胸腺上皮细胞上的I-Ab/I-Eb（IA-IE）表达。因此，IL-2、IL-12和IL-18的联合使用可诱导胸腺细胞发生表型和功能变化，这可能会改变胸腺内未成熟T细胞的迁移、分化和细胞死亡，并可能影响外周免疫区室中的Th1/Th2偏向。
