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Protection from septic shock by neutralization of macrophage migration inhibitory factor

Nature Medicine volume 6, pages 164–170 (2000)Cite this article

Abstract

Identification of new therapeutic targets for the management of septic shock remains imperative as all investigational therapies, including anti-tumor necrosis factor (TNF) and anti-interleukin (IL)-1 agents, have uniformly failed to lower the mortality of critically ill patients with severe sepsis. We report here that macrophage migration inhibitory factor (MIF) is a critical mediator of septic shock. High concentrations of MIF were detected in the peritoneal exudate fluid and in the systemic circulation of mice with bacterial peritonitis. Experiments performed in TNFα knockout mice allowed a direct evaluation of the part played by MIF in sepsis in the absence of this pivotal cytokine of inflammation. Anti-MIF antibody protected TNFα knockout from lethal peritonitis induced by cecal ligation and puncture (CLP), providing evidence of an intrinsic contribution of MIF to the pathogenesis of sepsis. Anti-MIF antibody also protected normal mice from lethal peritonitis induced by both CLP and Escherichia coli, even when treatment was started up to 8 hours after CLP. Conversely, co-injection of recombinant MIF and E. coli markedly increased the lethality of peritonitis. Finally, high concentrations of MIF were detected in the plasma of patients with severe sepsis or septic shock. These studies define a critical part for MIF in the pathogenesis of septic shock and identify a new target for therapeutic intervention.

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Figure 1: Kinetics of MIF appearance in peritoneal fluid and blood during E. coli peritonitis.
Figure 2: Monoclonal antibody against MIF protects TNFα-deficient mice from fulminant septic shock induced by cecal ligation and puncture (CLP).
Figure 3: Monoclonal antibody against MIF protects against lethal peritonitis induced by cecal ligation and puncture (CLP) when given before and after challenge.
Figure 4: Antibody against MIF protects against lethal E. coli peritonitis.
Figure 5: MIF potentiates lethality of E. coli peritonitis.
Figure 6: Boxplots of the plasma concentrations of MIF of healthy individuals (controls) (n=6) and of patients with either severe sepsis (n=7) or septic shock (n=9 ).

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Acknowledgements

We thank M. Knaup and S. Rossier for technical assistance, and T. Roger and P. Majcherczyk for critical reading of the manuscript.This work was supported by grants from the Swiss National Science Foundation to T.C. and to J.P., and by grants from the BMBF to D.M., and from the National Institutes of Health to R.B. T.C. is recipient of a career award from the Swiss National Science Foundation. M.P.G. is recipient of a career award from the Bristol-Myers Squibb Foundation. J.P. is the recipient of a fellowship from the Prof. Dr. Max Cloetta Foundation.

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Authors and Affiliations

  1. Division of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, Lausanne, CH-1011, Switzerland

    Thierry Calandra, Didier Le Roy, Didier Heumann & Michel P. Glauser

  2. Department of Pathology, Tumorimmunology, University of Regensburg, Regensburg, D-93042, Germany

    Bernd Echtenacher & Daniela Männel

  3. Division of Medical Intensive Care, Department of Medicine University Hospital Geneva, Geneva, 14, CH-1211, Switzerland

    Jérôme Pugin

  4. Laboratorie of Vascular Biology, The Picower Institute for Medical Research, Manhasset, 11030, New York, USA

    Christine N. Metz

  5. Forschungszentrum für Umwelt und Gesundheit-Institut für Experimentelle Hämatologie, München, D-81337, Germany

    Lothar Hültner

  6. Laboratorie of Medical Biochemistry, The Picower Institute for Medical Research, Manhasset, 11030, New York, USA

    Richard Bucala

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  1. Thierry Calandra
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Correspondence to Thierry Calandra.

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Calandra, T., Echtenacher, B., Roy, D. et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 6, 164–170 (2000). https://doi.org/10.1038/72262

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