A-Disintegrin and Metalloproteinase (ADAM) 17 Enzymatically Degrades Interferon-gamma

Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that exerts anti-tumor and anti-osteoclastogenic effects. Although transcriptional and post-transcriptional regulation of IFN-gamma is well understood, subsequent modifications of secreted IFN-gamma 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-gamma and attenuates IFN-gamma-mediated anti-tumorigenic and anti-osteoclastogenic effects. Recombinant ADAM17 degraded IFN-gamma into small fragments. The addition of ADAM17 to the culture supernatant of stimulated mouse splenocytes decreased IFN-gamma concentration. However, ADAM17 inhibition in the stimulated mouse T-cells prevented IFN-gamma degradation. ADAM17-expressing human breast cancer cell lines MCF-7 and MDA-MB-453 also degraded recombinant IFN-gamma, but this was attenuated by ADAM17 inhibition. Degraded IFN-gamma lost the functionality including the inhibititory effect on osteoclastogenesis. This is the first study to demonstrate the extracellular proteolytic degradation of IFN-gamma by ADAM17. These results suggest that ADAM17-mediated degradation of IFN-gamma may block the anti-tumorigenic and anti-osteoclastogenic effects of IFN-gamma. ADAM17 inhibition may be useful for the treatment of attenuated cancer immune surveillance and/or bone metastases.