Mechanistic differences between migration inhibitory factor (MIF) and IFN-gamma for macrophage activation. MIF and IFN-gamma synergize with lipid A to mediate migration inhibition but only IFN-gamma induces production of TNF-alpha and nitric oxide

• Published in: The Journal of immunology (1950) Vol. 150; no. 10; pp. 4524 - 4531
• Main Authors: Herriott, MJ, Jiang, H, Stewart, CA, Fast, DJ, Leu, RW
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Am Assoc Immnol 15-05-1993; American Association of Immunologists
• Subjects: Amino Acid Oxidoreductases - genetics; Analysis of the immune response. Humoral and cellular immunity; Animals; Base Sequence; Biological and medical sciences; Cell Migration Inhibition; Cell Movement - drug effects; Drug Synergism; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Immunobiology; In Vitro Techniques; Interferon-gamma - pharmacology; Lipid A - pharmacology; Macrophage Activation - drug effects; Macrophage Migration-Inhibitory Factors - pharmacology; Male; Mice; Mice, Inbred C3H; Miscellaneous; Molecular Sequence Data; Nitric Oxide - metabolism; Nitric Oxide Synthase; Oligodeoxyribonucleotides - chemistry; Recombinant Proteins - pharmacology; Regulatory factors and their cellular receptors; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; Cytokine; Rodentia; Biosynthesis; Synergism; Biological activity; Vertebrata; Mammalia; Mouse; Migration inhibitory factor; Nitrogen monoxide; Mechanism of action; Comparative study; Tumor necrosis factor α; Gamma interferon; Macrophage
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.150.10.4524

Previously we found that murine macrophage migration inhibition (MMI) was mediated by IFN-gamma-priming and lipid A triggering. With the recent availability of human recombinant migration inhibitory factor (MIF), which is distinctly different from IFN-gamma and other cytokines, we have now attempted to explore possible mechanistic differences between IFN-gamma and MIF to mediate MMI. Neither MIF not IFN-gamma were active alone, but effectively primed murine inflammatory macrophages for subsequent triggering by lipid A to mediate MMI. A specific neutralizing antibody for rMIF abrogated MMI mediated only by MIF and not by IFN-gamma-primed macrophages. Distinct differences were also found between the mechanisms by which MIF and IFN-gamma synergized with lipid A for activation in that IFN-gamma-primed and lipid A triggered macrophages produced TNF and nitric oxide (NO), whereas MIF-primed cells did not. Macrophages primed with IFN-gamma and triggered by rTNF were inhibited in their migration, whereas MIF failed to synergize with rTNF for MMI. An inhibitor of NO production NG-monomethyl-L-arginine inhibited MMI mediated by higher activating concentrations of lipid A and by IFN-gamma-primed and lipid A triggered macrophages, but had no effect on MIF-primed cells in concert with lipid A for increased expression of both TNF-alpha mRNA and NO synthase mRNA. Taken together, our results indicate that both MIF and IFN-gamma prime macrophages to synergize with lipid A to mediate MMI but by different mechanisms. The activation process by IFN-gamma to mediate migration inhibition appears to resemble requirements for rendering macrophages tumor cytotoxic in the production of TNF for autocrine-mediated NO generation by primed macrophages. In contrast, MIF-mediated MMI was independent of requirements for either TNF or NO production.