title: Interleukin-10 induces transcription of the early promoter of human papillomavirus type 16 (HPV16) through the 5'-segment of the upstream regulatory region (URR).
abstract: The effects of various proinflammatory cytokines on the transcription of human papillomaviruses (HPVs) have been demonstrated. On the other hand, the role of anti-inflammatory cytokines has not been elaborated, despite the fact that levels of interleukin-10 (IL-10) have been found significantly elevated in cervical dysplasias or carcinomas as well as in the cervix of HIV-positive individuals. These conditions are also associated with elevated viral transcription. Thus, the impact of IL-10 on HPV transcription might be important in pathogenesis of cervical lesions in both immunocompetent or immunosuppressed individuals. In this paper we describe the effects of IL-10 on the transcription of HPV type 16. We found that treatment of HPV 16-positive cervical carcinoma cells with IL-10 increased mRNA levels of the E7 early gene at the level of transcription. Similarly, IL-10 significantly and dose-dependently induced the transcription from the HPV early promoter in a reporter system. Employing deletion mutants we determined that this induction is mapped to the 5' segment of the URR. Transient transfection of an antisense-STAT3-expression vector abolished IL-10-induced reporter activity as well as HPV 16 E7 expression. This suggests that STAT3 either directly binds to the URR and stimulates transcription or affects expression and/or binding of transcription factors that bind to the 5'-region. Our findings suggest a mechanism by which--in addition to its immunosuppressive effects--IL-10 might enhance persistence and progression of HPV-related lesions under conditions (e.g. dysplastic progression, HIV infection) when the cytokine expression in the cervical microenvironment changes.
authors.affiliation: Department of Microbiology/Immunology, The University of Texas Medical Branch, Galveston, TX 77555-1070, USA. aranyistvan@uams.edu
authors.forename: Istvan
authors.initials: I
authors.lastname: Arany
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Grattendick
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Tyring
mesh_terms: D024506:5' Flanking Region / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology / Q000494:pharmacology*; D009856:Oncogene Proteins, Viral / Q000187:drug effects / Q000235:genetics*; D027383:Papillomaviridae / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D050725:Papillomavirus E7 Proteins; D010957:Plasmids; D011401:Promoter Regions, Genetic / Q000187:drug effects; D018123:Receptors, Interleukin / Q000235:genetics; D053701:Receptors, Interleukin-10; D012045:Regulatory Sequences, Nucleic Acid / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D004268:DNA-Binding Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; C059731:oncogene protein E7, Human papillomavirus type 16; D016753:Interleukin-10