| RRC ID |
51839
|
| 著者 |
Kanzaki H, Shinohara F, Suzuki M, Wada S, Miyamoto Y, Yamaguchi Y, Katsumata Y, Makihira S, Kawai T, Taubman MA, Nakamura Y.
|
| タイトル |
A-Disintegrin and Metalloproteinase (ADAM) 17 Enzymatically Degrades Interferon-gamma.
|
| ジャーナル |
Sci Rep
|
| 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.
|
| 巻・号 |
6
|
| ページ |
32259
|
| 公開日 |
2016-8-30
|
| DOI |
10.1038/srep32259
|
| PII |
srep32259
|
| PMID |
27573075
|
| PMC |
PMC5004192
|
| MeSH |
ADAM17 Protein / genetics
ADAM17 Protein / immunology
ADAM17 Protein / metabolism*
Amino Acid Sequence
Animals
Antibodies, Monoclonal / immunology
Antibodies, Monoclonal / pharmacology
Antibodies, Neutralizing / immunology
Antibodies, Neutralizing / pharmacology
Breast Neoplasms / genetics
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Line, Tumor
Cells, Cultured
Humans
Interferon-gamma / genetics
Interferon-gamma / metabolism*
MCF-7 Cells
Mice
Mice, Inbred BALB C
Proteolysis / drug effects
RAW 264.7 Cells
RNA Interference
Recombinant Proteins / metabolism*
T-Lymphocytes / drug effects
T-Lymphocytes / metabolism*
|
| IF |
3.998
|
| 引用数 |
5
|
| リソース情報 |
| ヒト・動物細胞 |
MCF7(RCB1904)
MDA-MB-453(RCB1192)
RAW 264(RCB0535) |
