REGULATION OF EARLY GENE-EXPRESSION OF HUMAN PAPILLOMAVIRUS TYPE-16 BY INFLAMMATORY CYTOKINES

The host's immune reaction against human papillomavirus (H PV) infecti on remains poorly understood. Inflammatory cytokines undoubtedly play a key role through activating and coordinating the immune response. Ho wever, their direct interactions with the HPV genes remain unclear. In the present study, the effects of various inflammatory cytokines on H PV16 gene expression were investigated. In a CAT assay, tumor necrosis factor (TNF) alpha and interleukin-1 (IL-1) alpha were shown to repre ss HPV16 early gene expression at the transcriptional level through th e noncoding region (NCR), whereas IL-6 and interferon-gamma did not. I n Northern blot analysis, TNF and IL-1 were also shown to repress HPV1 6 E6/E7 mRNA expression in the HPV16-immortalized human keratinocyte c ell line. The TNF- and IL-1-responsive elements in the HPV16 NCR were determined to lie within the cell-type-specific enhancer, where there are several binding sites for nuclear factors involved in HPV16 early gene regulation, suggesting the participation of these factors in TNF and IL-1 regulations. Thus, TNF and IL-1 were shown to have antiviral effects on HPV through down-regulation of its gene transcription. This is the first demonstration that TNF and IL-1 are involved in HPV gene regulation. These functions of inflammatory cytokines are presumed to contribute to the host's defense against HPV infection. (C) 1994 Acad emic Press, Inc.