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Reversal of Established Rat Crescentic Glomerulonephritis by Blockade of Macrophage Migration Inhibitory Factor (MIF): Potential Role of MIF in Regulating Glucocorticoid Production

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Abstract

Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine that also counter-regulates glucocorticoid action. We investigated whether immunoneutralization of MIF could reverse established experimental crescentic glomerulonephritis and if this treatment could modulate endogenous glucocorticoid levels. Accelerated anti-GBM glomerulonephritis was induced in six littermate pairs of rats. Once crescentic disease was established on day 7, one animal in each pair was given a daily injection of neutralizing anti-MIF antibody (Ab) or irrelevant isotype control Ab for 14 days and then killed on day 21. In addition, a group of 6 animals was killed on day 7 of disease without any treatment. Animals receiving the control Ab exhibited a rapidly progressive glomerulonephritis with severe renal injury (proteinuria), loss of renal function (creatinine clearance), anemia, and marked histologic damage (including glomerular crescent formation), compared with animals killed on day 7 without treatment. In contrast, anti-MIF Ab treatment partially reversed the disease by restoring normal renal function and reducing histological damage compared with untreated animals killed on day 7 (p < 0.05). Interestingly, anti-MIF Ab treatment also prevented severe anemia (p < 0.05). Reversal of disease was associated with a significant reduction in leukocyte infiltration and activation and renal interleukin-1 (IL-1) production. Importantly, anti-MIF Ab treatment caused a significant increase in endogenous serum corticosterone levels, which correlated with the reversal of disease parameters. In conclusion, this study has demonstrated that blocking MIF activity can partially reverse established crescentic glomerulonephritis and suggests that MIF operates by both enhancing the cellular immune response and suppressing the endogenous anti-inflammatory glucocorticoid response.

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Acknowledgments

This study was supported by grants from the National Health and Medical Research Council of Australia (no. 9960106) and the National Institutes of Health (no. 13591). We are grateful to Ms. M. Lo for corticosterone assay.

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Authors and Affiliations

  1. The First Hospital, Sun Yat-Sen University of Medical Sciences, Ghongzhou, China

    Niansheng Yang

  2. Department of Nephrology, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria, 3168, Australia

    David J. Nikolic-Paterson, Wei Mu, Robert C. Atkins & Hui Y. Lan Ph.D.

  3. Institute for Reproduction and Development, Monash Medical Centre, Clayton, Victoria, Australia

    Andreas Meinhardt

  4. Department of Nephrology, Veterans General Hospital-Taipei, National Yang-Ming University, Taipei, Taiwan

    Yee-Yung Ng

  5. Picower Institute for Medical Research, Manhasset, New York, USA

    Christine Metz, Michael Bacher & Richard Bucala

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  1. Niansheng Yang
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  4. Wei Mu
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  10. Hui Y. Lan Ph.D.
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Correspondence to Hui Y. Lan Ph.D..

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Communicated by R. Bucala.

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Yang, N., Nikolic-Paterson, D.J., Ng, YY. et al. Reversal of Established Rat Crescentic Glomerulonephritis by Blockade of Macrophage Migration Inhibitory Factor (MIF): Potential Role of MIF in Regulating Glucocorticoid Production. Mol Med 4, 413–424 (1998). https://doi.org/10.1007/BF03401748

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