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.
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.
Herriott
M J
MJ
Oklahoma Medical Research Foundation, Noble Center for Biomedical Research, Oklahoma City 73104.
Jiang
H
H
Stewart
C A
CA
Fast
D J
DJ
Leu
R W
RW
D000594:Amino Acid Oxidoreductases / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000187:drug effects; D004357:Drug Synergism; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology*; D008050:Lipid A / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D008263:Macrophage Migration-Inhibitory Factors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D008050:Lipid A; D008263:Macrophage Migration-Inhibitory Factors; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases