Metallothionein treatment reduces proinflammatory cytokines IL-6 and TNF-alpha and apoptotic cell death during experimental autoimmune encephalomyelitis (EAE)

Experimental autoimmune encephalomyelitis (EAE) is an animal model for the human autoimmune disease multiple sclerosis (MS), Proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) a re considered important for induction and pathogenesis of EAE/MS disease, w hich is characterized by significant inflammation and neuroglial damage. We have recently shown that the exogenous administration of the antioxidant p rotein zinc-metallothionein-II (Zn-MT-II) significantly decreased the clini cal symptoms, mortality, and leukocyte infiltration of the CNS during EAE. However, it is not known how EAE progression is regulated nor how cytokine production and cell death can be reduced. We herewith demonstrate that trea tment with Zn-MT-II significantly decreased the CNS expression of IL-6 and TNF-alpha during EAE. Zn-MT-II treatment could also significantly reduce ap optotic cell death of neurons and oligodendrocytes during EAE, as judged by using TUNEL and immunoreactivity for cytochrome c and caspases 1 and 3. In contrast, the number of apoptotic lymphocytes and macrophages was less aff ected by Zn-RIT-II treatment. The Zn-MT-II-induced decrease in proinflammat ory cytokines and apoptosis during EAE could contribute to the reported dim inution of clinical symptoms and mortality in EAE-immunized rats receiving Zn-MT-II treatment. Our results demonstrate that MT-II reduces the CNS expr ession of proinflammatory cytokines and the number of apoptotic neurons dur ing EAE in vivo and that MT-II might be a potentially useful factor for tre atment of EAE/MS. (C) 2001 Academic Press.