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 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.
Bosco
M C
MC
Laboratory of Molecular Biology, G. Gaslini Institute, Genova, Italy. mbosco@tin.it
Rapisarda
A
A
Massazza
S
S
Melillo
G
G
Young
H
H
Varesio
L
L
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D054407:Chemokine CCL4; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D007502:Iron Chelating Agents / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010848:Picolinic Acids / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D015534:Trans-Activators / Q000276:immunology / Q000494:pharmacology; D014364:Tryptophan / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D054407:Chemokine CCL4; D007502:Iron Chelating Agents; D019402:Macrophage Inflammatory Proteins; D010848:Picolinic Acids; D012333:RNA, Messenger; D015534:Trans-Activators; D014364:Tryptophan; C030614:picolinic acid