| First Author | Yan I | Year | 2016 |
| Journal | J Leukoc Biol | Volume | 99 |
| Issue | 5 | Pages | 749-60 |
| PubMed ID | 26561568 | Mgi Jnum | J:243094 |
| Mgi Id | MGI:5907586 | Doi | 10.1189/jlb.3A0515-207R |
| Citation | Yan I, et al. (2016) ADAM17 controls IL-6 signaling by cleavage of the murine IL-6Ralpha from the cell surface of leukocytes during inflammatory responses. J Leukoc Biol 99(5):749-60 |
| abstractText | The cytokine IL-6 is part of a regulatory signaling network that controls immune responses. IL-6 binds either to the membrane-bound IL-6 receptor-alpha (classic signaling) or to the soluble IL-6 receptor-alpha (trans-signaling) to initiate signal transduction via gp130 activation. Because classic and trans-signaling of IL-6 fulfill different tasks during immune responses, controlled shedding of the membrane-bound IL-6 receptor-alpha from the surface of immune cells can be considered a central regulator of IL-6 function. The results from cell culture-based experiments have implicated both a disintegrin and metalloprotease 10 and a disintegrin and metalloprotease 17 in IL-6 receptor-alpha shedding. However, the nature of the protease mediating IL-6 receptor-alpha release in vivo is not yet known. We used hypomorphic a disintegrin and metalloprotease 17 mice and conditional a disintegrin and metalloprotease 10 knock-out mice to identify the natural protease of the murine IL-6 receptor-alpha. Circulating homeostatic soluble IL-6 receptor-alpha levels are not dependent on a disintegrin and metalloprotease 10 or 17 activity. However, during Listeria monocytogenes infection, IL-6 receptor-alpha cleavage by the alpha-secretase a disintegrin and metalloprotease 17 is rapidly induced from the surface of different leukocyte populations. In contrast, CD4-Cre-driven a disintegrin and metalloprotease 10 deletion in T cells did not influence IL-6 receptor-alpha shedding from these cells after L. monocytogenes infection. A disintegrin and metalloprotease 17 was also required for IL-6 receptor-alpha ectodomain cleavage and release during endotoxemia. These results demonstrate a novel physiologic role for a disintegrin and metalloprotease 17 in regulating murine IL-6 signals during inflammatory processes. |
