Macrophage migration inhibitory factor (MIF) regulates host responses to endotoxin through modulation of Toll-like receptor 4 (TLR4)

Abstract

The cytokine macrophage migration inhibitory factor (MIF) has emerged recently as an important mediator of inflammation and innate immunity. MIF is rapidly released by macrophages after stimulation with microbial products and pro-inflammatory cytokines and, in turn, stimulates the production of pro-inflammatory mediators by immune cells. Immunoneutralization of MIF or deletion of the Mif gene was shown to protect animals from lethal endotoxemia, staphylococcal toxic shock and septic shock in experimental models of bacterial peritonitis. To investigate the function of MIF in innate immunity, we studied the response of macrophages expressing reduced levels of MIF to microbial products. These cells were generated by transduction of an antisense MIF adenovirus or by stable transfection with an antisense MIF plasmid or were obtained from MIF-knockout mice. MIF-deficient macrophages were shown to be hyporesponsive to stimulation with LPS and Gram-negative bacteria. The defect was associated with a down-regulation of Toll-like receptor 4 (TLR4), the signal transducing molecule of the LPS receptor complex. Immunoneutralization of extracellular MIF decreased TLR4 expression and responses of macrophages to LPS, indicating that MIF may exert autocrine effects. These findings identify an important role for MIF in innate immunity and provide a rationale for the development of anti-MIF strategy for the treatment of patients with Gram-negative septic shock.

Inhibition of Macrophage Migration Inhibitory Factor Reduces Diabetic Nephropathy in Type II Diabetes Mice

“…Previous studies have recognized MIF as the first molecule to arrive at the inflammation site and the factor that likely determines the degree of cellular inflammation [21]. MIF is known to counter-regulate the immunosuppressive effects of steroids [7] and to over-regulate the expression of Toll-like receptor (TLR)-4 on antigen-presenting cells [29]. MIF has been implicated in both types of diabetes [32], and there is evidence linking MIF with DN.…”

Interaction of macrophage migration inhibitory factor with ceruloplasmin: role of labile copper ions

“…It is a pharmacological target for treatment of septic shock and cancer with specific antibodies (Willson 2003). MIF-blocking antibodies prevented the lethal effect in animals modeling septic shock, whereas MIFknockout mice are tolerant to lethal concentrations of lipopolysaccharide (LPS) (Bozza et al 1999;Roger et al 2003).…”

Regulation of Toll-like receptor 4 expression in mouse colon by macrophage migration inhibitory factor

“…In addition, antisense MIF suppresses TLR4 promoter activity and TNF production. Another study by Roger et al (2003) has also demonstrated that MIF regulates host responses to endotoxin through modulation of TLR4 in macrophages. MIF-deficient macrophages have revealed the down-regulation of TLR4 expression and hyporesponsiveness to stimulation with LPS or Gram-negative bacteria.…”