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.
Kim
So-Young
SY
Department of Neuroscience, Ewha Institute of Neuroscience and Medical Research Center, Ewha Womans University School of Medicine, Seoul, South Korea.
Choi
Eung-Chil
EC
Woo Jo
Yeong
Y
Henson
John W
JW
Kim
Hee-Sun
HS
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