Substance P-induced IL-12 production by murine macrophages.
Previous investigations in our laboratory have suggested that substance P (NK-1) receptor expression by macrophages contributes to the resistance against the intracellular bacterial pathogen, Salmonella. To investigate possible mechanisms for such resistance, macrophages were cultured with varying concentrations of a substance P agonist to investigate the ability of this neuropeptide to augment IL-12 expression. The substance P agonist was a potent inducer of both IL-12p35 and IL-12p40 mRNA expression in cultured macrophages. The kinetics of this response were maximal within 6 h and could be observed with concentrations of substance P agonist as low as 0.1 nM. The nonpeptide, substance P receptor antagonist, CP96-345, significantly blocked agonist-induced IL-12 mRNA expression, further demonstrating that this effect was mediated through an NK-1 receptor. Substance P agonist alone could stimulate substantial secretion of IL-12p40, but not IL-12p70, by cultured macrophages. Thus, the substance P agonist had the ability to augment IL-12p35 and IL-12p40 mRNA expression, but not to increase IL-12p70 secretion. Like IFN-gamma, we found that substance P could combine with LPS to significantly augment the secretion of bioactive IL-12p70. The costimulatory effects of substance P agonist plus LPS on IL-12 mRNA expression were additive; however, this combination resulted in synergistic secretion of IL-12p70 by macrophages. Together, these results demonstrate the ability of NK-1 receptors to signal IL-12 production by macrophages and suggest mechanisms for substance P-induced modulation of cellular immunity.
Kincy-Cain
T
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Department of Microbiology and Immunology, Tulane University Medical Center, New Orleans, LA 70112, USA.
Bost
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KL
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000187:drug effects; D013373:Substance P / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D000276:Adjuvants, Immunologic; D001713:Biphenyl Compounds; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018664:Interleukin-12; D013373:Substance P; C066892:CP 96345