Hillman G G, Puri R K, Kukuruga M A, Pontes J E, Haas G P
Department of Urology, Wayne State University School of Medicine, Detroit, MI.
Clin Exp Immunol. 1994 Jun;96(3):476-83. doi: 10.1111/j.1365-2249.1994.tb06054.x.
We have recently shown that human renal cell carcinoma (RCC) tumour lines express high-affinity IL-4 receptors. Binding of IL-4 to RCC cells induced a growth inhibition in the range of 20-68%. To enhance the growth inhibitory effect of IL-4, we have tested the effects of two additional cytokines capable of directly affecting tumour cell growth. IFN-gamma caused a significant inhibition of RCC tumour cell growth (up to 70%) in a dose-dependent manner, whereas the effect of TNF-alpha was more limited (0-20% inhibition). The addition of IL-4 to IFN-gamma on RCC cells sensitive to IL-4 induced a greater inhibition of cell growth than that seen with each cytokine alone. IL-4 and IFN-gamma rendered RCC cells more responsive to the inhibitory effect mediated by TNF-alpha. The combination of TNF-alpha with IL-4 and IFN-gamma induced an optimal growth inhibition (up to 90-98%) of RCC cells. In addition to a direct anti-proliferative effect, we have demonstrated that these cytokines can also enhance the expression of MHC antigens on the surface of RCC tumour cell lines which may render the cells more immunogenic. All RCC lines tested expressed class I antigens, but not class II antigens. IFN-gamma induced class II expression and up-regulated the expression of class I antigens on RCC cells. Class II antigen expression was detectable following 48 h incubation, and greater after 72 h with IFN-gamma. IL-4 minimally affected class I expression, whereas TNF-alpha up-regulated class I antigen expression. IL-4 or TNF-alpha did not induce class II expression. The combination of the three cytokines slightly augmented the up-regulation of class I and class II antigens observed with IFN-gamma alone. These observations confirm the direct interaction of IL-4, IFN-gamma and TNF-alpha with RCC tumour cells, both at the level of growth regulation and MHC antigen expression, and suggest a therapeutic potential of the combination of the three cytokines for renal cell carcinoma.
我们最近发现，人肾细胞癌（RCC）肿瘤细胞系表达高亲和力的白细胞介素-4（IL-4）受体。IL-4与RCC细胞结合可诱导20%-68%的生长抑制。为增强IL-4的生长抑制作用，我们测试了另外两种能够直接影响肿瘤细胞生长的细胞因子的作用。γ干扰素（IFN-γ）以剂量依赖方式显著抑制RCC肿瘤细胞生长（高达70%），而肿瘤坏死因子-α（TNF-α）的作用则较为有限（0%-20%抑制）。在对IL-4敏感的RCC细胞上，将IL-4与IFN-γ联合使用比单独使用每种细胞因子诱导的细胞生长抑制作用更强。IL-4和IFN-γ使RCC细胞对TNF-α介导的抑制作用更敏感。TNF-α与IL-4和IFN-γ联合使用可诱导RCC细胞产生最佳生长抑制（高达90%-98%）。除了直接的抗增殖作用外，我们还证明这些细胞因子还可增强RCC肿瘤细胞系表面主要组织相容性复合体（MHC）抗原的表达，这可能使细胞更具免疫原性。所有测试的RCC细胞系均表达I类抗原，但不表达II类抗原。IFN-γ诱导II类抗原表达，并上调RCC细胞上I类抗原的表达。孵育48小时后可检测到II类抗原表达，72小时后用IFN-γ处理表达量更高。IL-4对I类抗原表达影响最小，而TNF-α上调I类抗原表达。IL-4或TNF-α均不诱导II类抗原表达。三种细胞因子联合使用对I类和II类抗原上调作用比单独使用IFN-γ时略有增强。这些观察结果证实了IL-4、IFN-γ和TNF-α与RCC肿瘤细胞在生长调节和MHC抗原表达水平上的直接相互作用，并提示三种细胞因子联合使用对肾细胞癌具有治疗潜力。
