Infection with Theiler's murine encephalomyelitis virus directly induces proinflammatory cytokines in primary astrocytes via NF-kappaB activation: potential role for the initiation of demyelinating disease.
Theiler's virus infection in the central nervous system (CNS) induces a demyelinating disease very similar to human multiple sclerosis. We have assessed cytokine gene activation upon Theiler's murine encephalomyelitis virus (TMEV) infection and potential mechanisms in order to delineate the early events in viral infection that lead to immune-mediated demyelinating disease. Infection of SJL/J primary astrocyte cultures induces selective proinflammatory cytokine genes (interleukin-12p40 [IL-12p40], IL-1, IL-6, tumor necrosis factor alpha, and beta interferon [IFN-beta]) important in the innate immune response to infection. We find that TMEV-induced cytokine gene expression is mediated by the NF-kappaB pathway based on the early nuclear NF-kappaB translocation and suppression of cytokine activation in the presence of specific inhibitors of the NF-kappaB pathway. Further studies show this to be partly independent of dsRNA-dependent protein kinase (PKR) and IFN-alpha/beta pathways. Altogether, these results demonstrate that infection of astrocytes and other CNS-resident cells by TMEV provides the early NF-kappaB-mediated signals that directly activate various proinflammatory cytokine genes involved in the initiation and amplification of inflammatory responses in the CNS known to be critical for the development of immune-mediated demyelination.
Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
JoAnn P
JP
Palma
Daeho
D
Kwon
Neil A
NA
Clipstone
Byung S
BS
Kim
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000276:immunology / Q000821:virology*; D018188:Cardiovirus Infections / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000276:immunology* / Q000503:physiopathology* / Q000821:virology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D051379:Mice; D017628:Microglia / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism*; D009836:Oligodendroglia / Q000821:virology; D017945:Theilovirus / Q000472:pathogenicity*
D016207:Cytokines; D016328:NF-kappa B