Updyke L W, Yoon H L, Robinson J P, Kiorpes A L, Marcus C B, Pfeifer R W
Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
Toxicol Appl Pharmacol. 1991 Jul;109(3):391-8. doi: 10.1016/0041-008x(91)90002-v.
In this laboratory, 3-methylindole (3-MI), a pneumotoxic metabolite of L-tryptophan that forms in the digestive tract of humans and ruminants, has been demonstrated to be toxic to rat and mouse splenic cells both in vitro and in vivo. The present studies examine whether the reduction in nucleated splenic cells is associated with alterations in: (1) immune functioning (e.g., B and T cell mitogenic responses to lectins), (2) natural resistance (e.g., natural killer (NK) activity and cytokine release from macrophages (MPs)), or (3) the relative percentages of B and T cells in the remaining cells as determined by flow cytometric phenotyping. A dose-dependent decrease in splenic weight (24-46%) and nucleated cell numbers (54-73%) was observed 24 hr after intraperitoneal (ip) administration of 100-300 mg/kg 3-MI to B6C3F1 mice. At a dose of 300 mg/kg, the blastogenic response of splenic lymphocytes to 1 microgram/ml phytohemagglutinin, a T cell mitogen, was reduced 37 and 64%, and NK activity was reduced 20 and 60%, in rats and mice, respectively. Following exposure to 400 mg/kg 3-MI, interleukin-1 and tumor necrosis factor production by lipopolysaccharide-stimulated rat splenic MPs was decreased 58 and 38%, respectively. Despite the reduction in total nucleated cell number in 3-MI-treated mice, the percentages of splenic B and T cells remained the same. These findings indicate that, in addition to its toxicity to splenic cells, 3-MI can significantly impair the functioning of the remaining viable cells. The potential importance of these functional changes for alterations in host resistance in rodents exposed to 3-MI or other alkylindoles is unknown.
在本实验室中，3-甲基吲哚（3-MI）是L-色氨酸的一种肺毒性代谢产物，在人和反刍动物的消化道中形成，已被证明在体外和体内对大鼠和小鼠的脾细胞均有毒性。本研究探讨有核脾细胞数量的减少是否与以下方面的改变有关：（1）免疫功能（例如，B细胞和T细胞对凝集素的促有丝分裂反应），（2）天然抵抗力（例如，自然杀伤（NK）活性和巨噬细胞（MPs）释放细胞因子），或（3）通过流式细胞术表型分析确定的剩余细胞中B细胞和T细胞的相对百分比。对B6C3F1小鼠腹腔注射（ip）100 - 300 mg/kg的3-MI后24小时，观察到脾脏重量（24 - 46%）和有核细胞数量（54 - 73%）呈剂量依赖性下降。在300 mg/kg的剂量下，大鼠和小鼠脾淋巴细胞对T细胞有丝分裂原1微克/毫升植物血凝素的增殖反应分别降低了37%和64%，NK活性分别降低了20%和60%。暴露于400 mg/kg的3-MI后，脂多糖刺激的大鼠脾MPs产生的白细胞介素-1和肿瘤坏死因子分别下降了58%和38%。尽管3-MI处理的小鼠中有核细胞总数减少，但脾脏B细胞和T细胞的百分比保持不变。这些发现表明，除了对脾细胞有毒性外，3-MI还可显著损害剩余活细胞的功能。这些功能变化对于暴露于3-MI或其他烷基吲哚的啮齿动物宿主抵抗力改变的潜在重要性尚不清楚。
