Human macrophage migration inhibitory factor: a proven immunomodulatory cytokine?
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory mediator with the ability to induce various immunomodulatory responses and override glucocorticoid-driven immunosuppression. Some of these functions have been linked to the unusual enzymatic properties of the protein, namely tautomerase and oxidoreductase activities. However, there are conflicting reports regarding the functional role of these enzymatic properties in normal physiological homeostasis and disease progression. Therefore, we have produced a highly pure, virtually endotoxin-free recombinant MIF preparation and fully characterized this using a variety of biochemical and biophysical approaches. The recombinant protein, with demonstrable enzymatic activity, was then used to systematically examine the biological activity of MIF. Surprisingly, treatment with MIF alone failed to induce cytokine expression, with the exception of IL-8. However, co-treatment of lipopolysaccharide (LPS) in conjunction with MIF produced synergistic secretion of tumor necrosis factor-alpha, interleukin (IL)-1, and IL-8 compared with LPS alone. The potentiating effect of MIF was seen at physiologically relevant concentrations. These data suggest that MIF has no conventional cytokine activity but, rather, acts to modulate and amplify the response to LPS.
Kudrin
Alex
A
Department of Disease Biology, Rheumatology, and Inflammation and Discovery Research, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom.
Scott
Martin
M
Martin
Steven
S
Chung
Chun-Wa
CW
Donn
Rachelle
R
McMaster
Andrew
A
Ellison
Stuart
S
Ray
David
D
Ray
Keith
K
Binks
Michael
M
D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology; D004357:Drug Synergism; D006098:Granulocytes / Q000166:cytology / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000737:chemistry / Q000302:isolation & purification* / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000302:isolation & purification* / Q000502:physiology*; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology
D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins