Antagonistic effect of picolinic acid and interferon-gamma on macrophage inflammatory protein-1alpha/beta 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.
Rapisarda
Annamaria
A
Laboratory of Molecular Biology, G. Gaslini Institute, 16147, Genoa, Italy.
Pastorino
Sandra
S
Massazza
Stefano
S
Varesio
Luigi
L
Bosco
Maria Carla
MC
D000818:Animals; D002461:Cell Line, Transformed / Q000187:drug effects; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D003864:Depression, Chemical; D004307:Dose-Response Relationship, Radiation; D005786:Gene Expression Regulation / Q000187:drug effects*; D006207:Half-Life; D007371:Interferon-gamma / Q000494:pharmacology*; D016753:Interleukin-10 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects* / Q000235:genetics; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010848:Picolinic Acids / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D010848:Picolinic Acids; D012333:RNA, Messenger; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; C030614:picolinic acid