Macrophage migration inhibitory factor (MIF) modulates innate immune responses induced by endotoxin and Gram-negative bacteria

Abstract

Discovered in the early 1960s as a T-cell cytokine, MIF has emerged to be an important mediator of the innate immune system. MIF was identified recently to be released by a vast array of cells, including monocytes/macrophages, T-cells, B-cells, endocrine cells and epithelial cells in response to infection and stress. Bacteria, microbial toxins and cytokines have been shown to be powerful inducers of MIF secretion by macrophages. MIF stimulates the expression of pro-inflammatory mediators by immune cells and functions to counterbalance the anti-inflammatory and immunosuppressive effects of glucocorticoids. Like TNF and IL-1, MIF plays an important role in host responses to infection. Recombinant MIF was found to exacerbate lethal endotoxemia or bacterial sepsis when co-injected with LPS or Escherichia coli in mice. Conversely, MIF knockout mice or mice treated with anti-MIF antibodies were protected from shock induced by LPS, staphylococcal exotoxins or bacterial peritonitis, even when anti-MIF therapy was started after the onset of infection. Given the central role played by MIF in innate immune responses against microbial pathogens and in the regulation of inflammatory responses, pharmacological modulation of MIF production or neutralization of MIF activity could have broad clinical applications and may offer new treatment options for the management of patients with severe sepsis or septic shock.

References

Bloom BR , Bennett B. Mechanism of a reaction in vitro associated with delayed-type hypersensitivity . Science 1966; 153: 80—82.

David J. Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. Proc Natl Acad Sci USA 1966; 56: 72—77.

Weiser WY , Temple PA , Witek-Gianotti JS , Remold HG , Clark SC , David JR Molecular cloning of a cDNA encoding a human macrophage migration inhibitory factor. Proc Natl Acad Sci USA 1989; 86: 7522—7526.

Bernhagen J. , Calandra T. , Mitchell RA et al. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 1993; 365: 756—759.

Calandra T. , Bernhagen J. , Mitchell RA , Bucala R. The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med 1994 ; 179: 1895—1902.

Calandra T. , Spiegel LA , Metz CN , Bucala R. Macrophage migration inhibitory factor (MIF) is a critical mediator of the activation of immune cells by exotoxins of Gram-positive bacteria. Proc Natl Acad Sci USA 1998; 95: 11383—11388.

Bacher M. , Metz CN , Calandra T. et al. An essential regulatory role for macrophage migration inhibitory factor in T-cell activation. Proc Natl Acad Sci USA 1996; 93: 7849—7854.

Calandra T. , Bernhagen J. , Metz CN et al. MIF as a glucocorticoid-induced modulator of cytokine production . Nature 1995; 377: 68—71.

Donnelly SC , Haslett C. , Reid PT et al. Regulatory role for macrophage migration inhibitory factor in acute respiratory distress syndrome. Nat Med 1997 ; 3: 320—323.

10.

Calandra T. , Echtenacher B. , Roy DL et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 2000; 6: 164—170.

11.

Zanetti G. , Heumann D. , Gerain J. et al. Cytokine production after intravenous or peritoneal Gram-negative bacterial challenge in mice. Comparative protective efficacy of antibodies to tumor necrosis factor-α and to lipopolysaccharide. J Immunol 1992; 148: 1890—1897.

12.

Bacher M. , Meinhardt A. , Lan HY et al. MIF expression in experimentally-induced endotoxemia. Am J Pathol 1997; 150: 235—246.

13.

Bozza M. , Satoskar AR , Lin G. et al. Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis. J Exp Med 1999 ; 189: 341—346.

14.

Kohler J. , Heumann D. , Garotta G. et al. IFN-gamma involvement in the severity of Gram-negative infections in mice. J Immunol 1993; 151: 916—921.

15.

Echtenacher B. , Falk W. , Männel DN , Krammer PH Requirement of endogenous tumor necrosis factor/cachectin for recovery from experimental peritonitis. J Immunol 1990; 145: 3762—3766.

16.

Heumann D. , Le Roy D. , Zanetti G. et al. Contribution of TNF/TNF receptor and of Fas ligand to toxicity in murine models of endotoxemia and bacterial peritonitis. J Inflamm 1999; 47: 173—179.

17.

Rothe J. , Lesslauer W. , Lötscher H. et al. Mice lacking the tumor necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes . Nature 1993; 364: 798—802.

18.

Pfeffer K. , Matsuyama T. , Kündig TM et al. Mice deficient for the 55 kD tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection . Cell 1993; 73: 457—467.