The tryptophan catabolite picolinic acid selectively induces the chemokines macrophage inflammatory protein-1α and-1β in macrophages
The tryptophan catabolite picolinic acid selectively induces the chemokines macrophage inflammatory protein-1α and-1β in macrophages
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DOI：
10.4049/jimmunol.164.6.3283
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发表时间：
2000-03-15
影响因子：
4.4
通讯作者：
Varesio, L
中科院分区：
文献类型：
--
作者：
Bosco, MC;Rapisarda, A;Varesio, L
我们先前发现色氨酸分解代谢产物吡啶甲酸(PA)是一种激活巨噬细胞效应功能的共刺激因子。在这项研究中，我们研究了PA调节巨噬细胞趋化因子表达的能力。我们证明PA是炎性趋化因子MIP(巨噬细胞炎性蛋白)-1α和MIP-1β(MIPs)在小鼠巨噬细胞中表达的有效激活剂，并以剂量和时间依赖的方式以及通过从头蛋白质合成依赖的过程。PA对MIPs的刺激作用在3h内达到高峰，对MIPs的刺激作用具有选择性，其他趋化因子如单核细胞趋化蛋白-1、RANTES、干扰素-γ诱导蛋白-10、MIP-2、巨噬细胞衍生趋化因子等在相同的实验条件下不被诱导，也不是巨噬细胞活化的表观现象，因为干扰素-γ不影响MIPs的表达。PA对MIP-1α和MIP-1β的诱导与转录激活和mRNA稳定有关，提示了控制的双重分子机制。铁络合可能参与了PA诱导MIPs的过程，因为硫酸铁抑制了这一过程和铁；螯合剂去铁胺诱导了MIPs的表达，我们提出了一种新的途径，导致由色氨酸分解代谢引发的炎症，该途径可以通过产生PA与免疫系统进行沟通，然后由巨噬细胞分泌趋化因子，这些结果证实了PA作为巨噬细胞促炎功能的激活剂的重要性，首次证明了这种分子可以在不需要共刺激剂的情况下具有生物活性。
We previously found that the tryptophan catabolite picolinic acid (PA) is a costimulus for the activation of macrophage effector functions. In this study, we have investigated the ability of PA to modulate the expression of chemokines in macrophages. We demonstrate that PA is a potent activator of the inflammatory chemokines MIP (macrophage inflammatory protein)-1 alpha and MIP-1 beta (MIPs) mRNA expression in mouse macrophages in a dose- and time-dependent fashion and through a de novo protein synthesis-dependent process. The induction by PA occurred within 3 h of treatment and reached a peak in 12 h, The stimulatory effects of PA were selective for MIPs because other chemokines, including monocyte chemoattractant protein-1, RANTES, IFN-gamma-inducible protein-10, MIP-2, and macrophage-derived chemokine, were not induced under the same experimental conditions and were not an epiphenomenon of macrophage activation because IFN-gamma did not affect MIPs expression. Induction of both MIP-1 alpha and MIP-1 beta by PA was associated with transcriptional activation and mRNA stabilization, suggesting a dual molecular mechanism of control. Iron chelation could be involved in MIPs induction by PA because iron sulfate inhibited the process and the iron;chelating agent, desferrioxamine, induced MIPs expression, We propose the existence of a new pathway leading to inflammation initiated by tryptophan catabolism that can communicate with the immune system through the production of PA, followed by secretion of chemokines by macrophages, These results establish the importance of PA as an activator of macrophage proinflammatory functions, providing the first evidence that this molecule can be biologically active without the need for a costimulatory agent.