Transcriptional activation of JC virus early promoter by phorbol ester and interleukin-1beta: critical role of nuclear factor-1.
JC virus causes the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML) under immunosuppressive states such as AIDS. During the pathogenesis of AIDS, HIV-infected microglia secrete cytokines including interleukin-1 and tumor necrosis factor-alpha (TNF-alpha), which affect neuronal cells resulting in dysfunction of the CNS. We hypothesized that extracellular stimuli released from HIV-infected microglia may reactivate JC virus by affecting neighboring oligodendrocytes. In the present study, we found that phorbol myristate acetate (PMA) and interleukin-1beta (IL-1beta) dramatically increased JC virus transcription in glial cells. Site-directed mutagenesis and gel shift analyses revealed that PMA and IL-1beta strongly induced nuclear factor-1 (NF-1) binding to the JC virus enhancer region, increasing transcriptional activity of the viral early promoter. Additionally, we demonstrated that protein kinase C (PKC) pathways were involved in the PMA/IL-1beta-mediated up-regulation of the JC virus early promoter. These findings may represent one of the possible mechanisms for higher incidence of PML among AIDS patients.
Department of Neuroscience, Ewha Institute of Neuroscience and Medical Research Center, Ewha Womans University School of Medicine, Seoul, South Korea.
So-Young
SY
Kim
Eung-Chil
EC
Choi
Yeong
Y
Woo Jo
John W
JW
Henson
Hee-Sun
HS
Kim
D001483:Base Sequence; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007577:JC Virus / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D051839:NFI Transcription Factors; D010703:Phorbol Esters / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects*
D022762:CCAAT-Enhancer-Binding Proteins; D007375:Interleukin-1; D051839:NFI Transcription Factors; D010703:Phorbol Esters; D014157:Transcription Factors