The Mycobacterium avium subsp. paratuberculosis fibronectin attachment protein, a toll-like receptor 4 agonist, enhances dendritic cell-based cancer vaccine potency.

Kyung Tae Noh; Sung Jae Shin; Kwang Hee Son; In Duk Jung; Hyun Kyu Kang; Su Jung Lee; Eun Kyung Lee; Yong Kyoo Shin; Ji Chang You; Yeong-Min Park

doi:22322306

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The Mycobacterium avium subsp. paratuberculosis fibronectin attachment protein, a toll-like receptor 4 agonist, enhances dendritic cell-based cancer vaccine potency.

Authors: Kyung Tae Noh ; Sung Jae Shin ; Kwang Hee Son ; In Duk Jung ; Hyun Kyu Kang ; Su Jung Lee ; Eun Kyung Lee ; Yong Kyoo Shin ; Ji Chang You ; Yeong-Min Park

Citation: EXPERIMENTAL AND MOLECULAR MEDICINE, Vol.44(5) : 340-349, 2012

Journal Title: EXPERIMENTAL AND MOLECULAR MEDICINE

ISSN: 1226-3613

Issue Date: 2012

MeSH: Adhesins, Bacterial*/genetics ; Adhesins, Bacterial*/metabolism ; Animals ; CD8-Positive T-Lymphocytes/metabolism ; Cancer Vaccines*/therapeutic use ; Cell Proliferation ; Cytokines/metabolism ; Dendritic Cells/cytology* ; Disease Models, Animal ; Gene Expression Regulation ; Glycogen Synthase Kinase 3/metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Mycobacterium avium/genetics ; Mycobacterium avium/metabolism ; Paratuberculosis/metabolism ; Protein Binding ; Signal Transduction ; T-Lymphocytes, Cytotoxic/metabolism ; Thymoma*/genetics ; Thymoma*/metabolism ; Toll-Like Receptor 4*/agonists ; Toll-Like Receptor 4*/genetics ; Toll-Like Receptor 4*/metabolism

Keywords: Adhesins, Bacterial*/genetics ; Adhesins, Bacterial*/metabolism ; Animals ; CD8-Positive T-Lymphocytes/metabolism ; Cancer Vaccines*/therapeutic use ; Cell Proliferation ; Cytokines/metabolism ; Dendritic Cells/cytology* ; Disease Models, Animal ; Gene Expression Regulation ; Glycogen Synthase Kinase 3/metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Mycobacterium avium/genetics ; Mycobacterium avium/metabolism ; Paratuberculosis/metabolism ; Protein Binding ; Signal Transduction ; T-Lymphocytes, Cytotoxic/metabolism ; Thymoma*/genetics ; Thymoma*/metabolism ; Toll-Like Receptor 4*/agonists ; Toll-Like Receptor 4*/genetics ; Toll-Like Receptor 4*/metabolism

Abstract: In this study, we showed the direct interaction between Mycobacterium avium subsp. paratuberculosis fibronectin attachment protein (FAP) and toll-like receptor4 (TLR4) via co-localization and binding by using confocal microscopy and co-immunoprecipitation assays. FAP triggered the expression of pro- and antiinflammatory cytokines in a TLR4-dependent manner. In addition, FAP-induced cytokine expression in bone marrow-derived dendritic cells (BMDCs) was modulated in part by glycogen synthase kinase-3 (GSK-3). FAP-induced expression of CD80, CD86, major histocompatibility complex (MHC) class I, and MHC class II in TLR4(+/+) BMDCs was not observed in TLR4(-/-) BMDCs. Furthermore, FAP induced DC-mediated CD8(+) T cell proliferation and cytotoxic T lymphocyte (CTL) activity, and suppressed tumor growth with DC-based tumor vaccination in EG7 thymoma murine model. Taken together, these results indicate that the TLR4 agonist, FAP, a potential immunoadjuvant for DC-based cancer vaccination, improves the DC-based immune response via the TLR4 signaling pathway.