ADAM17 Activity and IL-6 Trans-Signaling in Inflammation and Cancer

Abstract

All ligands of the epidermal growth factor receptor (EGF-R) are transmembrane proteins, which need to be proteolytically cleaved in order to be systemically active. The major protease responsible for this cleavage is the membrane metalloprotease ADAM17, which also has been implicated in cleavage of TNFα and interleukin-6 (IL-6) receptor. It has been recently shown that in the absence of ADAM17, the main protease for EGF-R ligand processing, colon cancer formation is largely abrogated. Intriguingly, colon cancer formation depends on EGF-R activity on myeloid cells rather than on intestinal epithelial cells. A major activity of EGF-R on myeloid cells is the stimulation of IL-6 synthesis. Subsequently, IL-6 together with the ADAM17 shed soluble IL-6 receptor acts on intestinal epithelial cells via IL-6 trans-signaling to induce colon cancer formation, which can be blocked by the inhibitor of IL-6 trans-signaling, sgp130Fc. Blockade of IL-6 trans-signaling therefore offers a new therapeutic window downstream of the EGF-R for the treatment of colon cancer and possibly of other EGF-R related neoplastic diseases.

Targeting STAT3 and STAT5 in Cancer

“…Melanoma and causatively linked autoimmune diseases are directly tied to hyperactivation of STAT3/5 cascades, and dual/simultaneous targeting could reduce the overall disease burden [30]. For colon cancer-based therapies, upstream targeting of IL-6 trans-signalling was explored in the context of the ligand-releasing protease, ADAM17 [31]. Aggressive epithelial ovarian cancer was discussed relative to the STAT3/5 activating tumor microenvironment and their correlation to the persistence of recurrent neoplasms [32].…”

Blocking ADAM17 Function with a Monoclonal Antibody Improves Sepsis Survival in a Murine Model of Polymicrobial Sepsis

“…the ubiquitously expressed glycoprotein 130 [39]. We also examine the plasma levels of IL-6R in mice treated with ertapenem +/− MEDI3622 but did not observe a significant reduction at 24 h post-CLP ( Figure 3).…”

The Society for Immunotherapy of Cancer perspective on regulation of interleukin-6 signaling in COVID-19-related systemic inflammatory response

“…11 44 Expression of the membrane-bound form of IL-6R is largely restricted to hepatocytes, megakaryocytes and leukocytes, 45 yet two independent pathways generate a soluble form of the receptor: cleavage by membrane metalloproteinases, primarily ADAM10 and ADAM17, as well as alternative splicing. [45][46][47] Soluble IL-6/IL-6R receptor complex can also bind gp130, activating the downstream signaling cascade. The ubiquitous expression of gp130, which has been detected in all human tissues examined, underlies the pleiotropic effects of IL-6, and the near universal responsiveness to the cytokine across cell types.…”