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MIF regulates innate immune responses through modulation of Toll-like receptor 4

Abstract

Macrophages are pivotal effector cells of the innate immune system, which is vital for recognizing and eliminating invasive microbial pathogens1,2. When microbial products bind to pathogen-recognition receptors, macrophages become activated and release a broad array of cytokines3 that orchestrate the host innate and adaptive immune responses. Initially identified as a T-cell cytokine4,5, macrophage migration inhibitory factor (MIF) is also a macrophage cytokine and an important mediator of inflammation and sepsis6,7,8,9,10,11,12. Here we report that MIF is an essential regulator of macrophage responses to endotoxin (lipopolysaccharide) and Gram-negative bacteria. Compared with wild-type cells, MIF-deficient macrophages are hyporesponsive to lipopolysaccharide and Gram-negative bacteria, as shown by a profound reduction in the activity of NF-κB and the production of tumour-necrosis factor-α. This reduction is due to a downregulation of Toll-like receptor 4 (TLR4), the signal-transducing molecule of the lipopolysaccharide receptor complex, and is associated with decreased activity of transcription factor PU.1, which is required for optimal expression of the Tlr4 gene in myeloid cells. These findings identify an important role for MIF in innate immunity and provide a molecular basis for the resistance of MIF-deficient mice to endotoxic shock.

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Figure 1: Hyporesponsiveness of antisense MIF macrophages to activation by LPS and Gram-negative bacteria.
Figure 2: MIF regulates macrophage responses to LPS by modulating the expression of TLR4.
Figure 3: Decreased basal TLR4 expression and LPS-induced TNF-α production by MIF knockout (MIF-/-) macrophages.
Figure 4: Basal TLR4 promoter activity and PU.1 DNA-binding activity are reduced in antisense MIF RAW 264.7 macrophages.

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Acknowledgements

We thank M. Knaup and D. LeRoy for technical assistance, and I. Miconnet, P. Majcherczyk and C. Froidevaux for critically reading the manuscript. We are grateful to G. Waeber and to I. Matsumura for their gifts of antisense MIF mRNA and the MHC–PU.1 luciferase construct, respectively. We thank T. Yadomae and K. Miyake for providing monoclonal antibodies to mouse CD14 and TLR4–MD-2, respectively. This work was supported by a grant from the Swiss National Science Foundation to T.C. T.C. and M.P.G. are recipients of career awards from the Swiss National Science Foundation, the Leenards Foundation and the Bristol-Myers Squibb Foundation.

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Correspondence to Thierry Calandra.

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Roger, T., David, J., Glauser, M. et al. MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature 414, 920–924 (2001). https://doi.org/10.1038/414920a

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