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The Journal of Neuroscience, January 15, 2003, 23(2):481-492
Interleukin-6 Protects Anterior Horn Neurons from Lethal
Virus-Induced Injury
Kevin D.
Pavelko1,
Charles L.
Howe1,
Kristen
M.
Drescher2,
Jeff D.
Gamez1,
Aaron J.
Johnson1,
Tao
Wei3,
Richard M.
Ransohoff3, and
Moses
Rodriguez1
1 Departments of Immunology and Neurology, Mayo Clinic,
Rochester, Minnesota 55905, 2 Department of Medical
Microbiology and Immunology, Creighton University, Omaha, Nebraska
68178, and 3 Department of Neurosciences, Lerner Research
Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195
We evaluated the role of interleukin-6 (IL-6) in neuronal injury
after CNS infection.
IL-6 / and
IL-6+/+ mice of resistant major histocompatibility
complex (MHC) H-2b haplotype intracerebrally
infected with Theiler's virus cleared the infection normally without
development of viral persistence, lethal neuronal infection, or late
phase demyelination. In contrast, infection of
IL-6/ mice
on a susceptible H-2q haplotype resulted in frequent
deaths and severe neurologic deficits within 2 weeks of infection as
compared with infected IL-6+/+
H-2q littermate controls. Morphologic analysis
demonstrated dramatic injury to anterior horn neurons of
IL-6/
H-2q mice at 12 d after infection. Infectious
viral titers in the CNS (brain and spinal cord combined) were
equivalent between
IL-6/
H-2q and IL-6+/+
H-2q mice. In contrast, more viral RNA was detected
in the spinal cord of
IL-6/ mice
compared with IL-6+/+ H-2q mice.
Virus antigen was localized predominantly to anterior horn cells in
infected
IL-6/
H-2q mice. IL-6 deletion did not affect the humoral
response directed against virus, nor did it affect the expression of
CD4, CD8, MHC class I, or MHC class II in the CNS. Importantly,
IL-6 was expressed by astrocytes of infected IL-6+/+
mice but not in astrocytes of
IL-6/ mice
or uninfected IL-6+/+ mice. Furthermore, expression
of various chemokines was robust at 12 d after infection in both
H-2b and H-2q
IL-6/
mice, indicating that intrinsic CNS inflammatory responses did not
depend on the presence of IL-6. Finally, in vitro
analysis of virus-induced death in neuroblastoma-spinal cord-34
motor neurons and primary anterior horn cell neurons showed that IL-6
exerted a neuroprotective effect. These data support the hypothesis
that IL-6 plays a critical role in protecting specific populations of
neurons from irreversible injury.
Key words:
Theiler's murine encephalomyelitis virus; interleukin-6; neuron; chemokine; CNS; multiple sclerosis
Copyright © 2003 Society for Neuroscience 0270-6474/03/232481-12$05.00/0
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