Induction of activator protein-1 and nuclear factor-kappaB as a prerequisite for disease development in susceptible SJL/J mice after theiler murine encephalomyelitis.

Theiler murine encephalomyelitis (TME) represents an important mouse model of multiple sclerosis. Activator protein and nuclear factor-kappaB proteins are interacting transcription factors controlling the expression of cytokines involved in the demyelination process. However, specific expression patterns of these transcription factors in susceptible and resistant mouse strains and their relationship to demyelination remains to be determined. The expression of activator protein-1 (c-fos and c-jun) and nuclear factor-kappaB (p50 and p65) genes, TME virus, tumor necrosis factor-alpha, and interferon-gamma was investigated in the spinal cord of TME virus (BeAn strain)-infected SJL/J and C57BL/6 mice until 196 days postinfection (dpi) using reverse transcription-quantitative polymerase chain reaction. Additionally, c-fos, c-jun, and p50 expression was examined by applying immunohistochemistry. In susceptible SJL/J mice, in contrast to resistant C57BL/6 mice, all investigated mRNA transcripts were upregulated in the early (0-7 days dpi) and late phases (28-196 days dpi) of TME. In addition, white matter lesions of SL/J mice were characterized by c-jun-positive astrocytes and p50-positive mononuclear immune cells. Upregulation of activator protein-1 and nuclear factor-kappaB in resident glial cells in the early phase followed by strong downstream tumor necrosis factor-alpha production might account for disease development in susceptible SJL/J mice. In the late phase, the formation of JUN/JUN homodimers in intralesional astrocytes might contribute to the sustained release of proinflammatory cytokines, thereby promoting disease progression.