Lejeune P, Lagadec P, Onier N, Pinard D, Ohshima H, Jeannin J F
INSERM U 252, Faculty of Medicine, Dijon, France.
J Immunol. 1994 May 15;152(10):5077-83.
The mechanisms of immunosuppression induced by colon cancer in rats were investigated at the systemic and tumor levels. During tumor growth (after i.p. injection of rat colon adenocarcinoma cells in syngeneic BD IX rats), Con A-induced proliferation of splenic mononuclear cells decreased and nitric oxide (NO) production by splenic macrophages increased concomitantly. Incubating splenic mononuclear cells with an inhibitor of NO synthase, NG-monomethyl-L-arginine, restored lymphocyte proliferation. A low level of inducible NO synthase mRNA was detectable in tumors by Northern blotting, with a weak increase during tumor growth. The NO concentration measured in the tumor nodules increased weakly parallel to the tumor growth. Five and six weeks after tumor cell injection, tumor-infiltrating lymphocytes from disaggregated tumors did not proliferate in the presence of Con A. Addition of NG-monomethyl-L-arginine inhibited the production of NO in tumor dissociations and enhanced tumor-infiltrating lymphocyte proliferation. Glyceryl trinitrate (a NO-releasing compound) totally inhibited the lymphocyte proliferation in vitro while it slightly reduced the tumor cell proliferation. T lymphocytes were therefore more sensitive to NO than were tumor cells. Culture medium from tumor cells induced NO production by splenic macrophages, although the factor involved has not yet been identified. Furthermore, tumor cells could also play a part in NO production by tumors because the tumor cells were induced to produce NO by IFN-gamma plus IL-1. These results strongly suggest the participation of NO in the tumor-induced immunosuppression in rats.
在全身和肿瘤水平上研究了大鼠结肠癌诱导免疫抑制的机制。在肿瘤生长过程中（将大鼠结肠腺癌细胞腹腔注射到同基因BD IX大鼠后），伴刀豆球蛋白A诱导的脾单核细胞增殖减少，同时脾巨噬细胞产生的一氧化氮（NO）增加。用NO合酶抑制剂NG-单甲基-L-精氨酸孵育脾单核细胞可恢复淋巴细胞增殖。通过Northern印迹法在肿瘤中可检测到低水平的诱导型NO合酶mRNA，在肿瘤生长过程中略有增加。在肿瘤结节中测得的NO浓度与肿瘤生长呈微弱平行增加。肿瘤细胞注射后五周和六周，来自解离肿瘤的肿瘤浸润淋巴细胞在伴刀豆球蛋白A存在下不增殖。添加NG-单甲基-L-精氨酸可抑制肿瘤解离物中NO的产生并增强肿瘤浸润淋巴细胞的增殖。硝酸甘油（一种释放NO的化合物）在体外完全抑制淋巴细胞增殖，同时略微降低肿瘤细胞增殖。因此，T淋巴细胞比肿瘤细胞对NO更敏感。肿瘤细胞的培养基可诱导脾巨噬细胞产生NO，尽管尚未确定其中涉及的因子。此外，肿瘤细胞也可能参与肿瘤中NO的产生，因为肿瘤细胞被γ干扰素加白细胞介素-1诱导产生NO。这些结果强烈表明NO参与了大鼠肿瘤诱导的免疫抑制。
