Melillo G, Cox G W, Radzioch D, Varesio L
Laboratory of Molecular Immunoregulation, National Cancer Institute-Frederick Cancer Research and Development Center, NIH, MD 21702-1201.
J Immunol. 1993 May 1;150(9):4031-40.
In this study we investigated the effects of picolinic acid, a catabolite of L-tryptophan, on the production of L-arginine-derived reactive nitrogen intermediates in the murine macrophage cell line ANA-1. ANA-1 macrophages did not produce nitrite (NO2-) constitutively, but accumulated detectable levels of NO2- on exposure to IFN-gamma. Picolinic acid, although ineffective by itself, augmented IFN-gamma-induced NO2- production. The activity of picolinic acid was evident at 1 mM and reached its maximum at 4 mM. Picolinic acid also augmented the IFN-gamma-dependent expression of TNF-alpha mRNA, but did not appreciably affect the secretion of the TNF-alpha protein. Neutralizing concentrations of anti-TNF mAb completely abrogated IFN-gamma- and IFN-gamma plus rTNF-alpha-induced NO2- production in ANA-1 macrophages, but only decreased by approximately 50% the synergistic interaction between IFN-gamma and picolinic acid. Although IL-4 inhibited the expression of IFN-gamma plus picolinic acid-induced TNF-alpha mRNA and protein, it only partially suppressed picolinic acid-dependent NO2- production. Therefore, picolinic acid may affect NO2- production via both TNF-alpha-dependent and TNF-alpha-independent pathways. Overall, this study suggests that amino acid catabolites may be important for the activation and the expression of effector functions by murine macrophages, and provides the first evidence of a possible connection between tryptophan and arginine metabolism.
在本研究中，我们调查了L-色氨酸的分解代谢产物吡啶甲酸对小鼠巨噬细胞系ANA-1中L-精氨酸衍生的活性氮中间体产生的影响。ANA-1巨噬细胞组成性地不产生亚硝酸盐（NO2-），但在暴露于IFN-γ时会积累可检测水平的NO2-。吡啶甲酸虽然自身无效，但能增强IFN-γ诱导的NO2-产生。吡啶甲酸的活性在1 mM时明显，在4 mM时达到最大值。吡啶甲酸还增强了IFN-γ依赖性的TNF-α mRNA表达，但对TNF-α蛋白的分泌没有明显影响。中和浓度的抗TNF单克隆抗体完全消除了ANA-1巨噬细胞中IFN-γ和IFN-γ加rTNF-α诱导的NO2-产生，但仅使IFN-γ与吡啶甲酸之间的协同相互作用降低了约50%。虽然IL-4抑制了IFN-γ加吡啶甲酸诱导的TNF-α mRNA和蛋白的表达，但它仅部分抑制了吡啶甲酸依赖性的NO2-产生。因此，吡啶甲酸可能通过TNF-α依赖性和TNF-α非依赖性途径影响NO2-产生。总体而言，本研究表明氨基酸分解代谢产物可能对小鼠巨噬细胞的激活和效应功能的表达很重要，并提供了色氨酸与精氨酸代谢之间可能联系的首个证据。
