Carlin J M, Borden E C, Sondel P M, Byrne G I
Department of Human Oncology, University of Wisconsin Medical School, Madison 53706.
J Immunol. 1987 Oct 1;139(7):2414-8.
Degradation of tryptophan to kynurenine, catalyzed by indoleamine 2,3-dioxygenase (IDO), has been augmented in human epithelial cell lines treated with human interferon-gamma (HuIFN-gamma). Several human biologic response modifiers, including HuIFN-gamma, HuIFN-beta, HuIFN-alpha, interleukin 2 (HuIL-2), and tumor necrosis factor alpha, have now been assessed for their ability to enhance tryptophan degradation in human peripheral blood mononuclear cell (PMC) cultures. PMC were isolated from normal donors, cultivated in RPMI 1640 medium containing [3H]tryptophan, and treated with individual biologic response modifiers. At various intervals, culture supernatants were removed, fractionated by reversed-phase high performance liquid chromatography, and radioactivity in resultant fractions was determined. Significantly increased amounts of tryptophan catabolites were observed after treatment with HuIFN-gamma, HuIFN-beta, HuIFN-alpha, and HuIL-2, but not human tumor necrosis factor alpha. Often, greater than 30% of available tryptophan was degraded by treated PMC cultures. Although antibodies to HuIFN-alpha, HuIFN-beta, and HuIFN-gamma specifically neutralized the induction of IDO activity in PMC by their respective HuIFN, only anti-HuIFN-gamma antibody also neutralized HuIL-2-induced IDO activity. Furthermore, T24 bladder carcinoma cells, in which IDO was induced by HuIFN-gamma but not by the other biologic response modifiers, were induced to degrade tryptophan by supernatants of HuIL-2-stimulated PMC cultures, but not by HuIFN-beta-stimulated PMC culture supernatants. Thus, whereas HuIL-2 indirectly induced IDO in PMC cultures by stimulating production of HuIFN-gamma, all cases of interferons appeared to induce IDO directly in PMC cultures.
在用人干扰素-γ（HuIFN-γ）处理的人上皮细胞系中，由吲哚胺2,3-双加氧酶（IDO）催化的色氨酸向犬尿氨酸的降解作用增强。现在已经评估了几种人类生物反应调节剂，包括HuIFN-γ、HuIFN-β、HuIFN-α、白细胞介素2（HuIL-2）和肿瘤坏死因子α，增强人外周血单个核细胞（PMC）培养物中色氨酸降解的能力。从正常供体中分离出PMC，在含有[3H]色氨酸的RPMI 1640培养基中培养，并用单个生物反应调节剂进行处理。在不同时间间隔，去除培养上清液，通过反相高效液相色谱法进行分离，并测定所得馏分中的放射性。在用HuIFN-γ、HuIFN-β、HuIFN-α和HuIL-2处理后，观察到色氨酸分解代谢产物的量显著增加，但人肿瘤坏死因子α处理后未观察到。通常，经处理的PMC培养物可降解超过30%的可用色氨酸。尽管针对HuIFN-α、HuIFN-β和HuIFN-γ的抗体可特异性中和各自HuIFN对PMC中IDO活性的诱导作用，但只有抗HuIFN-γ抗体也能中和HuIL-2诱导的IDO活性。此外，HuIFN-γ可诱导T24膀胱癌细胞中IDO的表达，而其他生物反应调节剂则不能，HuIL-2刺激的PMC培养物上清液可诱导T24膀胱癌细胞降解色氨酸，而HuIFN-β刺激的PMC培养物上清液则不能。因此，虽然HuIL-2通过刺激HuIFN-γ的产生间接诱导PMC培养物中的IDO，但所有干扰素似乎都能直接在PMC培养物中诱导IDO。
