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Journal of Virology, October 2004, p. 11152-11160, Vol. 78, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.20.11152-11160.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Papillomavirus-Like Particles Stimulate Murine Bone Marrow-Derived Dendritic Cells To Produce Alpha Interferon and Th1 Immune Responses via MyD88

Departments of Pathology,¹ Molecular Biology & Genetics,² Pediatrics,⁵ Gynecology & Obstetrics,⁶ Flow Cytometry Facility, The Johns Hopkins School of Medicine, Baltimore, Maryland,³ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan⁴

Received 19 May 2004/ Accepted 10 June 2004

Dendritic cells (DCs) link innate and adaptive immunity by sensing pathogens or vaccinogens and signaling a variety of defense responses. Since human papillomavirus type 16 L1 virus-like particles (HPV16 VLPs) induce a potent, protective immune response after vaccination, we examined their recognition by DCs. HPV16 VLPs cause phenotypic maturation of murine bone marrow-derived DCs (BMDCs), and immunization of mice with HPV16 VLP-loaded BMDCs or HPV16 VLPs alone induced T helper 1 (Th1)-biased immune responses. Analysis of transcriptional responses of murine BMDCs by microarray suggested that alpha/beta interferon (IFN-/ß) transcripts and numerous proinflammatory cytokines and chemokines are up regulated in response to HPV16 VLPs. Indeed, the induction of IFN-, IFN-, and interleukin-12 (IL-12) production by BMDCs after stimulation with HPV16 VLPs was demonstrated by quantitative enzyme-linked immunosorbent assay. Many microbial products that induce proinflammatory responses are recognized via Toll-like receptor (TLR) signaling through the key adaptor protein MyD88 and activation of NF-B, nuclear factor of activated T cells (NF-AT), and activating protein 1 (AP-1). Reporter assays indicated that HPV16 VLPs activated NF-B-, NF-AT-, and AP-1-dependent transcription in the RAW264.7 macrophage cell line. Knockdown of MyD88 transcripts by small interfering RNA in the RAW264.7 macrophage cell line inhibited the activation of NF-B-, NF-AT- and AP-1-dependent transcription by HPV16 VLP. Furthermore, MyD88^–/– BMDCs failed to up regulate IL-12 and IFN- and - in response to HPV16 VLPs. Finally, Th1-biased immune responses to HPV16 VLPs are dramatically impaired in MyD88 and IFN-/ß receptor-deficient mice. This implicates TLR recognition as central to immune recognition of HPV16 L1 VLPs.

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