REGULATION OF HUMAN T CELL FUNCTIONS BY INTERLEUKIN 12 (IL-12)

白细胞介素 12 (IL-12) 对人类 T 细胞功能的调节

• 批准号: 2456633
• 负责人: R. P DONNELLY
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2456633
• 关键词: CD3 molecule; T lymphocyte; human tissue; immunoregulation; interferon gamma; interleukin 10; interleukin 12; interleukin 2; leukocyte activation /transformation; lymphoblast; protein biosynthesis; tumor necrosis factor alpha

It is well known that IL-12 up-regulates synthesis of interferon-gamma (IFN-g) in activated T cells; however, the effects of IL-12 on expression of other cytokines are not well defined. In this project, we are examining the effects of IL-12 on production of multiple cytokines, including IFN-g, IL-2, IL-10 and tumor necrosis factor-a (TNF-a), by purified, normal human CD3+ T cells. Although resting T cells are largely IL-12-nonresponsive, anti-CD3-activated T cell blasts are highly IL-12-responsive as demonstrated by the ability of IL-12 to induce Stat4-mediated gamma-interferon response region (GRR) DNA-binding activity. We have found that activation of purified human T lymphoblasts on immobilized anti-CD3 mAb induces rapid expression of TNF-a mRNA, and a more gradual increase in mRNA levels for IL-2, IFN-g and IL-10. IL-12 markedly up-regulates expression of IFN-g and IL-10, and down-regulates production of IL-2. Inhibition of IL-2 production by IL-12 correlates directly with increased production of IL-10. Moreover, neutralization of IL-10 activity with anti-IL-10 antibodies normalizes IL-2 production in IL-12-treated T cells demonstrating that the inhibitory effects of IL-12 are IL-10-mediated. Thus, IL-12 simultaneously up-regulates production of IFN-g and IL-10, and, by a direct IL-10-dependent pathway, feedback inhibits production of IL-2. The fact that IL-12 differentially regulates synthesis of IFN-g and IL-2 in T cells demonstrates that IL-12 does not globally enhance expression of all Th1-type lymphokines. Furthermore, the ability of IL-12 to up-regulate production of IL-10 provides a mechanism for limiting IL-2-dependent clonal expansion of activated T cells, and defines a novel cytokine regulatory pathway that is inducible by IL-12. In future studies, we plan to further define the effects of IL-12 on cytokine production by activated T cells, and to compare the effects of IL-12 with that of other macrophage-derived immunoregulatory cytokines, particularly IL-1 beta and TNF-alpha. We will also further explore the functional consequences of increased IL-10 production in IL-12-treated T cells. The results of these studies will broaden our present understanding of the actions of IL-12 on immune effector cells. This information may be useful in interpreting any therapeutic activity induced by IL-12 in clinical trials now underway. It may also provide insight to the physiological basis for certain toxicities associated with high dose IL-12 therapy.

众所周知，IL-12上调干扰素-γ的合成 在活化的T细胞中，IL-12对IFN-γ表达的影响是不明显的。 其他细胞因子的作用尚不明确。 在这个项目中，我们 检测IL-12对多种细胞因子产生的影响， 包括IFN-γ、IL-2、IL-10和肿瘤坏死因子-α（TNF-α）， 纯化的正常人CD 3 + T细胞。 尽管静息T细胞 在很大程度上，IL-12非应答性、抗CD 3活化的T细胞母细胞是高度 IL-12应答性，如通过IL-12诱导 Stat 4介导的γ-干扰素反应区（GRR）DNA结合 活动 我们已经发现纯化的人T淋巴母细胞的活化 固定的抗CD 3 mAb诱导TNF-α mRNA的快速表达， IL-2、IFN-g和IL-10的mRNA水平更逐渐增加。 IL-12 显著上调IFN-γ和IL-10的表达，下调IFN-γ和IL-10的表达。 生产IL-2。 IL-12对IL-2产生的抑制相关 与IL-10的产生直接相关。 此外， 用抗IL-10抗体降低IL-10活性使IL-2产生正常化 在IL-12处理的T细胞中，证实了 IL-12是IL-10介导的。 因此，IL-12同时上调 IFN-γ和IL-10的产生，并且，通过直接的IL-10依赖性途径， 反馈抑制IL-2的产生。 事实上，IL-12的差异 调节T细胞中IFN-γ和IL-2的合成表明IL-12 并不全面增强所有Th 1型淋巴因子的表达。 此外，IL-12上调IL-10产生的能力与IL-12的表达有关。 提供了一种限制IL-2依赖性克隆扩增的机制， 激活T细胞，并定义了一种新的细胞因子调节途径， 可被IL-12诱导。 在未来的研究中，我们计划进一步定义 IL-12对活化的T细胞产生细胞因子的作用，以及 比较IL-12与其他巨噬细胞源性 免疫调节细胞因子，特别是IL-1 β和TNF-α。 我们 还将进一步探索IL-10增加的功能后果， 在IL-12处理的T细胞中产生。 这些研究的结果将 拓宽了我们目前对IL-12在免疫中作用的理解， 效应细胞 这些信息可能有助于解释任何 IL-12诱导的治疗活性的临床试验正在进行中。 它也可以提供洞察力的生理基础，某些 与高剂量IL-12治疗相关的毒性。