The tryptophan catabolite picolinic acid selectively induces the chemokines macrophage inflammatory protein-1 alpha and-1 beta in macrophages

We previously found that the tryptophan catabolite picolinic acid (PA) is a costimulus for the activation of macrophage effector functions. In this st udy, we have investigated the ability of PA to modulate the expression of c hemokines in macrophages. We demonstrate that PA is a potent activator of t he inflammatory chemokines MIP (macrophage inflammatory protein)-1 alpha an d MIP-1 beta (MIPs) mRNA expression in mouse macrophages in a dose- and tim e-dependent fashion and through a de novo protein synthesis-dependent proce ss. 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 oth er chemokines, including monocyte chemoattractant protein-1, RANTES, IFN-ga mma-inducible protein-10, MIP-2, and macrophage-derived chemokine, were not induced under the same experimental conditions and were not an epiphenomen on of macrophage activation because IFN-gamma did not affect MIPs expressio n. Induction of both MIP-1 alpha and MIP-1 beta by PA was associated with t ranscriptional activation and mRNA stabilization, suggesting a dual molecul ar mechanism of control. Iron chelation could be involved in MIPs induction by PA because iron sulfate inhibited the process and the iron;chelating ag ent, desferrioxamine, induced MIPs expression, We propose the existence of a new pathway leading to inflammation initiated by tryptophan catabolism th at can communicate with the immune system through the production of PA, fol lowed by secretion of chemokines by macrophages, These results establish th e 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.