Yu W G, Yamamoto N, Takenaka H, Mu J, Tai X G, Zou J P, Ogawa M, Tsutsui T, Wijesuriya R, Yoshida R, Herrmann S, Fujiwara H, Hamaoka T
Biomedical Research Center, Osaka University, Medical School, 2-2, Yamada-oka, Suita, Osaka 565, Japan.
Int Immunol. 1996 Jun;8(6):855-65. doi: 10.1093/intimm/8.6.855.
The present study investigates the molecular mechanisms by which IFN-gamma produced as a result of in vivo IL-12 administration exerts its anti-tumor effects. rIL-12 was administered three or five times into mice bearing CSA1M fibrosarcoma, OV-HM ovarian carcinoma or MCH-1-A1 fibrosarcoma. This regimen induced complete regression of CSA1M and OV-HM tumors but only transient growth inhibition of MCH-1-A1 tumors. The anti-tumor effects of IL-12 were associated with enhanced induction of IFN-gamma because these effects were abrogated by pretreatment of hosts with anti-IFN-gamma antibody. Exposure in vitro of the three types of tumor cells to rRFN-gamma resulted in moderate to potent inhibition of tumor cell growth. IFN-gamma stimulated the expression of mRNAs for an inducible type of NO synthase (iNOS) in CSA1M cells and indoleamine 2,3-dioxygenase (IDO), an enzyme capable of degrading tryptophan, in OH-HM cells, but induced only marginal levels of these mRNAs in MCH-1-A1 cells. In association with iNOS gene expression, IFN-gamma-stimulated CSA1M cells produced a large amount of NO which functioned to inhibit their own growth in vitro. Although OV-HM and MCH-1A1 cells did not produce NO, they also exhibited NO susceptibility. Whereas the tumor masses from IL-12-treated CSA1M-bearing or OV-HM-bearing mice induced higher levels of iNOS (for CSA1M) or IDO and iNOS (for OV-HM) mRNAs, the MCH-1-A1 tumor mass expressed lower levels of iNOS mRNA alone. Moreover, massive infiltration of CD4(+) and CD8(+) T cells and Mac-1(+) cells was seen only in the CSA1M and OV-HM tumors. Thus, these results indicate that IFN-gamma produced after IL-12 treatment induces the expression of various genes with potential to modulate tumor cell growth by acting directly on tumor cells or stimulating tumor-infiltrating lymphoid cells and that the effectiveness of IL-12 therapy is associated with the operation of these mechanisms.
本研究调查了体内给予白细胞介素-12（IL-12）后产生的γ干扰素（IFN-γ）发挥其抗肿瘤作用的分子机制。将重组IL-12（rIL-12）给携带CSA1M纤维肉瘤、OV-HM卵巢癌或MCH-1-A1纤维肉瘤的小鼠注射3次或5次。该方案可使CSA1M和OV-HM肿瘤完全消退，但对MCH-1-A1肿瘤仅产生短暂的生长抑制。IL-12的抗肿瘤作用与IFN-γ的诱导增强有关，因为用抗IFN-γ抗体预处理宿主可消除这些作用。三种类型的肿瘤细胞在体外暴露于rIFN-γ后，导致肿瘤细胞生长受到中度至强效抑制。IFN-γ刺激CSA1M细胞中诱导型一氧化氮合酶（iNOS）的mRNA表达，并刺激OH-HM细胞中吲哚胺2,3-双加氧酶（IDO，一种能够降解色氨酸的酶）的mRNA表达，但在MCH-1-A1细胞中仅诱导这些mRNA的微量表达。与iNOS基因表达相关，IFN-γ刺激的CSA1M细胞产生大量一氧化氮，其作用是在体外抑制自身生长。虽然OV-HM和MCH-1A1细胞不产生一氧化氮，但它们也表现出对一氧化氮的敏感性。来自接受IL-12治疗的携带CSA1M或OV-HM小鼠的肿瘤块诱导更高水平的iNOS（对于CSA1M）或IDO和iNOS（对于OV-HM）mRNA，而MCH-1-A1肿瘤块仅表达较低水平的iNOS mRNA。此外，仅在CSA1M和OV-HM肿瘤中观察到CD4(+)和CD8(+) T细胞以及Mac-1(+)细胞的大量浸润。因此，这些结果表明，IL-12治疗后产生的IFN-γ通过直接作用于肿瘤细胞或刺激肿瘤浸润淋巴细胞来诱导各种具有调节肿瘤细胞生长潜力的基因表达，并且IL-12治疗的有效性与这些机制的运作有关。
