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The Journal of Neuroscience, November 22, 2006, 26(47):12174-12185; doi:10.1523/JNEUROSCI.2289-06.2006

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Neurobiology of Disease
Interleukin-11 Potentiates Oligodendrocyte Survival and Maturation, and Myelin Formation

Yueting Zhang,^1,2 Carla Taveggia,³ Carmen Melendez-Vasquez,³ Steven Einheber,⁴ Cedric S. Raine,^5,6 James L. Salzer,³ Celia F. Brosnan,^5,6 and Gareth R. John^1,2,5

¹Corinne Goldsmith Dickinson Center for Multiple Sclerosis and ²Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, ³Department of Cell Biology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, ⁴Hunter College School of Health Sciences, New York, New York 10010, and Departments of ⁵Pathology (Neuropathology) and ⁶Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461

Correspondence should be addressed to Dr. Gareth R. John, Department of Neurology, Annenberg 14-86, Box 11-37, Mount Sinai School of Medicine, New York, NY 10029. Email: gareth.john{at}mssm.edu

Mechanisms that regulate oligodendrocyte survival and myelin formation are an intense focus of research into myelin repair in the lesions of multiple sclerosis (MS). Although demyelination and oligodendrocyte loss are pathological hallmarks of the disease, increased oligodendrocyte numbers and remyelination are frequently observed in early lesions, but these diminish as the disease course progresses. In the current study, we used a microarray-based approach to investigate genes regulating repair in MS lesions, and identified interleukin-11 (IL-11) as an astrocyte-derived factor that potentiates oligodendrocyte survival and maturation, and myelin formation. IL-11 was induced in human astrocyte cultures by the cytokines IL-1 and TGF1, which are both prominently expressed in MS plaques. In MS tissue samples, IL-11 was expressed by reactive astrocytes, with expression particularly localized at the myelinated border of both active and silent lesions. Its receptor, IL-11R, was expressed by oligodendrocytes. In experiments in human cultures in vitro, IL-11R localized to immature oligodendrocytes, and its expression decreased during maturation. In cultures treated with IL-11, we observed a significant increase in oligodendrocyte number, and this was associated with enhanced oligodendrocyte survival and maturation. Importantly, we also found that IL-11 treatment was associated with significantly increased myelin formation in rodent CNS cocultures. These data are the first to implicate IL-11 in oligodendrocyte viability, maturation, and myelination. We suggest that this pathway may represent a potential therapeutic target for oligodendrocyte protection and remyelination in MS.

Key words: astrocyte; cytokine; myelin; multiple sclerosis; oligodendrocyte; repair

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Received Oct. 17, 2005; revised Sept. 11, 2006; accepted Oct. 4, 2006.

Correspondence should be addressed to Dr. Gareth R. John, Department of Neurology, Annenberg 14-86, Box 11-37, Mount Sinai School of Medicine, New York, NY 10029. Email: gareth.john{at}mssm.edu

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