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.
Original language | English (US) |
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Pages (from-to) | 32259 |
Journal | Scientific Reports |
Volume | 6 |
DOIs | |
State | Published - Aug 30 2016 |
Externally published | Yes |
Keywords
- ADAM17 Protein/genetics
- Amino Acid Sequence
- Animals
- Antibodies, Monoclonal/immunology
- Antibodies, Neutralizing/immunology
- Breast Neoplasms/genetics
- Cell Line, Tumor
- Cells, Cultured
- Humans
- Interferon-gamma/genetics
- MCF-7 Cells
- Mice
- Mice, Inbred BALB C
- Proteolysis/drug effects
- RAW 264.7 Cells
- RNA Interference
- Recombinant Proteins/metabolism
- T-Lymphocytes/drug effects