Interleukin-11 potentiates oligodendrocyte survival and maturation, and myelin formation.
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-1beta and TGFbeta1, 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 alpha, was expressed by oligodendrocytes. In experiments in human cultures in vitro, IL-11R alpha 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.
Zhang
Yueting
Y
Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai School of Medicine, New York, New York 10029, USA.
Taveggia
Carla
C
Melendez-Vasquez
Carmen
C
Einheber
Steven
S
Raine
Cedric S
CS
Salzer
James L
JL
Brosnan
Celia F
CF
John
Gareth R
GR
D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002470:Cell Survival / Q000187:drug effects; D002490:Central Nervous System / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005333:Fetus; D005455:Fluorescent Antibody Technique / Q000379:methods; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D017370:Interleukin-11 / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology; D046228:Microarray Analysis / Q000379:methods; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009186:Myelin Sheath / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D009836:Oligodendroglia / Q000187:drug effects* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D046509:Tissue Culture Techniques; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D017370:Interleukin-11; D053583:Interleukin-1beta; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D001973:Bromodeoxyuridine