Antagonistic effect of picolinic acid and interferon-γ on macrophage inflammatory protein-1α/β production

The L-tryptophan catabolite, picolinic acid (PA), is an activator of macrophage effector functions and an inducer of macrophage inflammatory protein-1alpha (MIP-1alpha) and -1beta (MIPs). We have investigated the regulation of PA-induced MIPs production in mouse macrophages. We demonstrated a dose- and time-dependent downregulation of MIPs mRNA by the Th1 cytokine, IFN-gamma, that was associated with inhibition of intracellular chemokine production and secretion. This effect was IFN-gamma-specific because MIPs induction was unaffected by the Th2 cytokines, IL-10 and IL-4, or the proinflammatory stimulus, LPS. Moreover, MIPs downregulation by IFN-gamma was dependent on both mRNA destabilization and gene transcription inhibition. These results demonstrate that MIP-1alpha/beta production by macrophages is a tightly regulated process resulting from the interaction between inhibitory stimuli derived from the immune system and stimulatory signals of non-immunologic origin. The antagonistic effect of PA and IFN-gamma on MIPs production may be important for the regulation of the inflammatory responses in vivo.