The Journal of Experimental Medicine
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Published online 1 January 2001.
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© The Rockefeller University Press, 0022-1007/2001/1/111/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 1, January 1, 2001 111-122

Original Article

Caspase-11 Mediates Oligodendrocyte Cell Death and Pathogenesis of Autoimmune-Mediated Demyelination

Shin Hisaharaa, Junying Yuanc, Takashi Momoid, Hideyuki Okanoa,b, and Masayuki Miuraa,b,e

a Division of Neuroanatomy, Department of Neuroscience, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
b Core Research for Evolutional Science and Technology (CREST), Osaka 565-0871, Japan
c Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115
d Division of Development and Differentiation, National Institute of Neuroscience, Tokyo 187-8502, Japan
e Laboratory for Cell Recovery Mechanisms, Brain Science Institute, RIKEN, Saitama 351-0198, Japan
Laboratory for Cell Recovery Mechanisms, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.81-48-467-694681-48-467-6945

miura{at}brain.riken.go.jp

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas of demyelination. The mechanisms underlying oligodendrocyte (OLG) injury in MS and EAE remain unknown. Here we show that caspase-11 plays crucial roles in OLG death and pathogenesis in EAE. Caspase-11 and activated caspase-3 were both expressed in OLGs in spinal cord EAE lesions. OLGs from caspase-11–deficient mice were highly resistant to the cell death induced by cytotoxic cytokines. EAE susceptibility and cytokine concentrations in the CNS were significantly reduced in caspase-11–deficient mice. Our findings suggest that OLG death is mediated by a pathway that involves caspases-11 and -3 and leads to the demyelination observed in EAE.

Key Words: apoptosis • cytokines • experimental autoimmune encephalomyelitis • multiple sclerosis • knockout mouse

Abbreviations used in this paper: ALP, alkaline phosphatase; CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; FBS, fetal bovine serum; GST, glutathione S-transferase; IGIF, IFN-{gamma} inducing factor; MBP, myelin basic protein; MOG, myelin OLG glycoprotein; MS, multiple sclerosis; OLG, oligodendrocyte.

© 2001 The Rockefeller University Press


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