Regulation of tumor necrosis factor alpha promoter by human parvovirus B19 NS1 through activation of AP-1 and AP-2.
Human parvovirus B19 frequently causes acute and chronic arthritis in adults. The molecular mechanism of B19 arthritis, however, remains poorly understood. We previously showed that the transmission of B19 from rheumatoid synoviocytes to monocytic cells is associated with enhanced secretion of tumor necrosis factor alpha (TNF-alpha), which triggers inflammation, and interleukin-6. To determine the role of B19 in the production of TNF-alpha, we focused on the function of its nonstructural protein, NS1, and established monocytic U937 lines transduced with the NS1 gene under the control of an inducible promoter. Production of TNF-alpha mRNA and protein was elevated in a manner associated with NS1 expression. Reporter assays revealed that AP-1 and AP-2 motifs on the TNF-alpha promoter were responsible for NS1-mediated up-regulation. Electrophoretic mobility shift assay showed specific binding of nuclear proteins from NS1 gene-transduced cells with the AP-1 or AP-2 probe. Antibodies against transcription factors AP-1 and AP-2 and anti-NS1 antibody inhibited the binding of nuclear proteins to the corresponding probes. These data indicate that NS1 up-regulates TNF-alpha transcription via activation of AP-1 and AP-2 in monocytic cells. The molecular mechanisms of NS1-mediated TNF-alpha expression would explain the pathogenesis of B19-associated inflammation.
Fu
Yi
Y
Division of Rheumatology and Hematology, Department of Clinical Medicine, Tohoku University School of Medicine, Sendai 980-8574, Japan.
Ishii
Keiko Kumura
KK
Munakata
Yasuhiko
Y
Saitoh
Takako
T
Kaku
Mitsuo
M
Sasaki
Takeshi
T
D004268:DNA-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D016732:Parvovirus B19, Human / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020218:Response Elements; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*; D020298:U937 Cells; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C106202:NS1 protein, parvovirus; D009687:Nuclear Proteins; D018808:Transcription Factor AP-1; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D017361:Viral Nonstructural Proteins