title: A-Disintegrin and Metalloproteinase (ADAM) 17 Enzymatically Degrades Interferon-gamma.
abstract: Interferon-gamma (IFN-γ) is a pleiotropic cytokine that exerts anti-tumor and anti-osteoclastogenic effects. Although transcriptional and post-transcriptional regulation of IFN-γ is well understood, subsequent modifications of secreted IFN-γ are not fully elucidated. Previous research indicates that some cancer cells escape immune surveillance and metastasize into bone tissue by inducing osteoclastic bone resorption. Peptidases of the a-disintegrin and metalloproteinase (ADAM) family are implicated in cancer cell proliferation and tumor progression. We hypothesized that the ADAM enzymes expressed by cancer cells degrades IFN-γ and attenuates IFN-γ-mediated anti-tumorigenic and anti-osteoclastogenic effects. Recombinant ADAM17 degraded IFN-γ into small fragments. The addition of ADAM17 to the culture supernatant of stimulated mouse splenocytes decreased IFN-γ concentration. However, ADAM17 inhibition in the stimulated mouse T-cells prevented IFN-γ degradation. ADAM17-expressing human breast cancer cell lines MCF-7 and MDA-MB-453 also degraded recombinant IFN-γ, but this was attenuated by ADAM17 inhibition. Degraded IFN-γ lost the functionality including the inhibititory effect on osteoclastogenesis. This is the first study to demonstrate the extracellular proteolytic degradation of IFN-γ by ADAM17. These results suggest that ADAM17-mediated degradation of IFN-γ may block the anti-tumorigenic and anti-osteoclastogenic effects of IFN-γ. ADAM17 inhibition may be useful for the treatment of attenuated cancer immune surveillance and/or bone metastases.
authors: Department of Orthodontics, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa pref., 230-8501, Japan.|Tohoku University Hospital, Maxillo-Oral Disorders, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi pref. 980-8575, Japan.
authors: Hiroyuki
authors: H
authors: Kanzaki
authors: Tohoku University Graduate School of Dentistry, Oral Microbiology, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi pref. 980-8575, Japan.
authors: Fumiaki
authors: F
authors: Shinohara
authors: The Forsyth Institute, Department of Immunology and Infectious Diseases, 245 First Street, Cambridge, MA, 02142, USA.|Department Mineralized Tissue Biology, 245 First Street, Cambridge, MA 02142, USA.
authors: Maiko
authors: M
authors: Suzuki
authors: Department of Orthodontics, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa pref., 230-8501, Japan.
authors: Satoshi
authors: S
authors: Wada
authors: Department of Orthodontics, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa pref., 230-8501, Japan.
authors: Yutaka
authors: Y
authors: Miyamoto
authors: Department of Orthodontics, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa pref., 230-8501, Japan.
authors: Yuuki
authors: Y
authors: Yamaguchi
authors: Department of Orthodontics, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa pref., 230-8501, Japan.
authors: Yuta
authors: Y
authors: Katsumata
authors: Section of Fixed Prosthodontics, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan.
authors: Seicho
authors: S
authors: Makihira
authors: The Forsyth Institute, Department of Immunology and Infectious Diseases, 245 First Street, Cambridge, MA, 02142, USA.|Harvard School of Dental Medicine, Department of Oral Medicine, Infection, and Immunity, Boston, MA 02115, USA.
authors: Toshi
authors: T
authors: Kawai
authors: The Forsyth Institute, Department of Immunology and Infectious Diseases, 245 First Street, Cambridge, MA, 02142, USA.|Harvard School of Dental Medicine, Department of Developmental Biology, Boston, MA 02115, USA.
authors: Martin A
authors: MA
authors: Taubman
authors: Department of Orthodontics, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa pref., 230-8501, Japan.
authors: Yoshiki
authors: Y
authors: Nakamura
mesh_terms: D000072198:ADAM17 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D059748:Proteolysis / Q000187:drug effects; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D011994:Recombinant Proteins; D007371:Interferon-gamma; D000072198:ADAM17 Protein