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LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival

Nature Medicine volume 8, pages 613–619 (2002)Cite this article

Abstract

Multiple sclerosis (MS) is a disabling inflammatory demyelinating disease of the central nervous system (CNS) that primarily affects young adults. Available therapies can inhibit the inflammatory component of MS but do not suppress progressive clinical disability. An alternative approach would be to inhibit mechanisms that drive the neuropathology of MS, which often includes the death of oligodendrocytes, the cells responsible for myelinating the CNS. Identification of molecular mechanisms that mediate the stress response of oligodendrocytes to optimize their survival would serve this need. This study shows that the neurotrophic cytokine leukemia inhibitory factor (LIF) directly prevents oligodendrocyte death in animal models of MS. We also demonstrate that this therapeutic effect complements endogenous LIF receptor signaling, which already serves to limit oligodendrocyte loss during immune attack. Our results provide a novel approach for the treatment of MS.

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Figure 1: Therapeutic effect of LIF in EAE.
Figure 2: LIF potentiates oligodendroglial survival without influencing inflammatory infiltration.
Figure 3: LIF induces signal transduction in EAE spinal cord.
Figure 4: Oligodendrocytes upregulate the expression of LIFR-β and STAT-3 in EAE.
Figure 5: Deleterious effect of reduced gp130/LIFR-β expression in MOG EAE.

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Acknowledgements

We thank the staff at our animal facilities for their help; R. Milekic for her secretarial support; and D. Advani for his support with graphic production. This work was funded in part by the Multiple Sclerosis Society of Australia and AMRAD. H.B. is the recipient of a National Health & Medical Research Council of Australia doctoral scholarship, and T.J.K. is the recipient of a Sylvia and Charles Viertel Charitable Trust Fellowship.

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Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Victoria, Australia

    Helmut Butzkueven, Jian-Guo Zhang, Merja Soilu-Hanninen, Hubertus Hochrein, Fiona Chionh, Kylie A. Shipham, Ben Emery, Ann M. Turnley, Steven Petratos, Perry F. Bartlett & Trevor J. Kilpatrick

  2. Ludwig Institute for Cancer Research, The Royal Melbourne Hospital, Victoria, Australia

    Matthias Ernst

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Correspondence to Trevor J. Kilpatrick.

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Competing interests

A patent covering potential therapeutic applications of LIF in neuroscience, is held by AMRAD Corporation. P.B. is named as an inventor on this patent. AMRAD Corporation has provided financial support for aspects of the described work, and T.K. has acted as a paid consultant to advise AMRAD Corporation on applications of LIF in neuroscience. None of the authors have any financial interest in AMRAD Corporation.

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Butzkueven, H., Zhang, JG., Soilu-Hanninen, M. et al. LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival. Nat Med 8, 613–619 (2002). https://doi.org/10.1038/nm0602-613

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