Castration of male C57L/J mice increases susceptibility and estrogen treatment restores resistance to Theiler's virus-induced demyelinating disease.
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Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelination in selective mouse strains. We have previously demonstrated that the males of C57L mice are significantly more susceptible to TMEV-induced demyelinating disease. To assess further the hormonal influence for this gender-associated differential susceptibility, estrogen-treated, castrated C57L mice were infected with TMEV and compared with sham-operated and/or placebo-treated mice. Interestingly, castration further elevated the susceptibility to virally induced demyelinating disease compared with sham-castrated control mice, and prolonged treatment of castrated mice with estrogen restored the resistance to the level of control mice. These results strongly suggest that sex hormone levels contribute to the gender-biased susceptibility to TMEV-induced demyelinating disease. Mice treated with estrogen showed a significantly decreased level of virus-specific Th1 responses both in the periphery and in the CNS. In addition, in vitro estrogen treatment was able to inhibit viral replication directly in macrophages, consistent with the lower level of viral RNA in microglia/macrophages in the CNS from castrated estrogen-treated mice compared with controls. Also, estrogen treatment inhibited VCAM-1 expression induced by tumor necrosis factor-alpha in cerebral vascular endothelial (CVE) cells via inhibition of nuclear factor-kappaB (NFkappaB), which is produced in various glial cells upon TMEV infection. Overall, estrogen treatment appears to exert its effects on viral replication, induction of immune responses, as well as infiltration of activated immune cells into the CNS via inhibition of NFkappaB function.