Ha S J, Lee C H, Lee S B, Kim C M, Jang K L, Shin H S, Sung Y C
Department of Life Science, Center for Biofunctional Molecules, Pohang University of Science and Technology, Kyungbuk, Korea.
J Immunol. 1999 Sep 1;163(5):2902-8.
IL-12p70 plays a pivotal role in regulating the Th1/Th2 balance in the initial stage of immune responses. In contrast, IL-12p40, which is produced excess over IL-12p70, has been known to down-regulate IL-12p70-mediated responses by acting as an antagonist. To investigate in vivo function of IL-12p40, RH7777 rat hepatoma cells were engineered to inducibly express mouse IL-12p40 under the tight control of doxycycline (dox). In the absence of dox, s.c. injection of these cells into syngeneic rat was shown to generate tumors. However, the induction of IL-12p40 by dox was sufficient for inhibiting tumor formation, as well as for tumor regression. Immunohistochemical analysis showed that macrophages, but not CD4+ T, CD8+ T, and NK cells, were predominantly recruited into tumor sites as early as 3 days after IL-12p40 induction. These results were further supported by the observation that IL-12p40, but not C-terminal deletion mutants by more than 5 amino acids, was able to chemoattract peritoneal macrophages in vitro, suggesting that IL-12p40, when produced in a large excess over IL-12p70 in vivo, can initially amplify the immune responses against tumors by directly recruiting macrophages. Our findings indicate that IL-12p40 may function as an effector molecule as well as an antagonist of IL-12p70.
白细胞介素-12p70在免疫反应初始阶段调节Th1/Th2平衡中起关键作用。相比之下，白细胞介素-12p40的产生量超过白细胞介素-12p70，已知它通过作为拮抗剂来下调白细胞介素-12p70介导的反应。为了研究白细胞介素-12p40的体内功能，对RH7777大鼠肝癌细胞进行工程改造，使其在强力霉素（dox）的严格控制下可诱导表达小鼠白细胞介素-12p40。在没有dox的情况下，将这些细胞皮下注射到同基因大鼠体内会形成肿瘤。然而，dox诱导白细胞介素-12p40足以抑制肿瘤形成以及使肿瘤消退。免疫组织化学分析表明，早在白细胞介素-12p40诱导后3天，巨噬细胞而非CD4⁺T细胞、CD8⁺T细胞和NK细胞就主要被募集到肿瘤部位。白细胞介素-12p40而非C末端缺失超过5个氨基酸的突变体能够在体外趋化腹膜巨噬细胞，这一观察结果进一步支持了上述结果，表明在体内白细胞介素-12p40的产生量大大超过白细胞介素-12p70时，它可通过直接募集巨噬细胞来最初放大针对肿瘤的免疫反应。我们的研究结果表明，白细胞介素-12p40可能既作为效应分子又作为白细胞介素-12p70的拮抗剂发挥作用。
