Ziai M R, Imberti L, Tongson A, Ferrone S
Cancer Res. 1985 Nov;45(11 Pt 2):5877-82.
By culture of human melanoma Colo 38 cells in the presence of increasing concentrations of recombinant immune interferon (IFN-gamma), the clone RZ gamma-4G.1 resistant to the antiproliferative action of IFN-gamma (3 X 10(4) units/ml) was isolated. This clone was cultured for 6 weeks in the absence of IFN-gamma and was subsequently treated with increasing concentrations of IFN-gamma. Contrary to the response of its parental cell line, treatment of this clone with IFN-gamma did not significantly alter the rate of protein or DNA synthesis and did not markedly modulate the cell surface expression of HLA Class I antigens, of the high molecular weight melanoma associated antigen, and of a Mr 100,000 melanoma associated antigen. IFN-gamma caused an increase in the cell surface expression and in the shedding of HLA Class II antigens from IFN-gamma resistant cells. Four proteins with molecular weights of 32,000, 38,000, 46,000, and 50,000 were induced by IFN-gamma in the parental melanoma cells but not in the resistant clone. Both cell lines bound equivalent amounts of 125I-IFN-gamma to their surface, indicating that the lack of specific surface receptors was not the cause of insensitivity to IFN-gamma. These results indicate that at the cellular level IFN-gamma modulates the expression and shedding of HLA Class II antigens through different mechanisms to those responsible for the antiproliferative action, modulation of the cell surface expression of melanoma associated antigen and of HLA Class I antigens, and induction of new proteins in cultured melanoma cells. Since the success of therapy of malignant diseases with IFN-gamma depends on the extent of resistance of individual tumor cells, the present study may provide a better understanding of the biology of IFN-gamma insensitive tumor cells and particularly the malignant melanoma.
通过在不断增加浓度的重组免疫干扰素（IFN-γ）存在的情况下培养人黑色素瘤Colo 38细胞，分离出了对IFN-γ（3×10⁴单位/毫升）的抗增殖作用具有抗性的克隆RZγ-4G.1。该克隆在无IFN-γ的情况下培养6周，随后用不断增加浓度的IFN-γ进行处理。与其亲代细胞系的反应相反，用IFN-γ处理该克隆并未显著改变蛋白质或DNA合成速率，也未明显调节HLA I类抗原、高分子量黑色素瘤相关抗原以及分子量为100,000的黑色素瘤相关抗原的细胞表面表达。IFN-γ导致IFN-γ抗性细胞的细胞表面HLA II类抗原表达增加以及其脱落。IFN-γ在亲代黑色素瘤细胞中诱导出分子量分别为32,000、38,000、46,000和50,000的四种蛋白质，但在抗性克隆中未诱导出。两种细胞系在其表面结合等量的¹²⁵I-IFN-γ，表明缺乏特异性表面受体不是对IFN-γ不敏感的原因。这些结果表明，在细胞水平上，IFN-γ通过与负责抗增殖作用、调节黑色素瘤相关抗原和HLA I类抗原的细胞表面表达以及在培养的黑色素瘤细胞中诱导新蛋白质的机制不同的机制，调节HLA II类抗原的表达和脱落。由于用IFN-γ治疗恶性疾病的成功取决于单个肿瘤细胞的耐药程度，本研究可能有助于更好地理解IFN-γ不敏感肿瘤细胞的生物学特性，尤其是恶性黑色素瘤。
