Macrophage activating properties of the tryptophan catabolite picolinic acid

Abstract

Recent studies have suggested a role for aminoacid catabolites as important regulators of macrophage (Mφ) activities. We reported previously that picolinic acid (PA), a tryptophan catabolite produced under inflammatory conditions and a costimulus with IFNγ of Mφ effector functions, is a selective inducer of the Mφ inflammatory protein-1α (MIP-1α) and -1β (MIPs), two CC-chemokines involved in the elicitation of the inflammatory reactions and in the development of the Th1 responses. In this study, we have investigated the effects of IFNγ on PA-induced MIPs expression and secretion by mouse Mφ as well as the regulation of MIP-1α/β receptor, CCR5, by both stimuli alone or in combination. We demonstrated that IFNγ inhibited MIPs mRNA stimulation by PA in a dose-and time-dependent fashion, despite its ability to induce other CC- or CXC chemokines. MIPs mRNA down-regulation was associated with decreased intracellular chemokine expression and secretion and was dependent on both mRNA destabilization and gene transcription inhibition. Moreover, IFNγ inhibitory effects were stimulus-specific because MIPs induction by PA was either unaffected or increased by the antiinflammatory cytokines, IL-10 and IL-4, or the pro-inflammatory stimulus, LPS, respectively. In contrast, we found that IFNγ increased CCR5 basal expression, whereas PA down-regulated both constitutive and IFNγ-induced CCR5 mRNA and protein levels. These results demonstrate that IFNγ and PA have reciprocal effects on the production of MIPs chemokines and the expression of their receptor. The concerted action of IFNγ and PA on MIP-1α/β chemokine/receptor system is likely to be of pathophysiological significance and to represent an important regulatory mechanism for leukocyte recruitment and distribution into damaged tissues during inflammatory responses.