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.
Highlights
IL-6 is a four-helical cytokine with pleiotropic activities, which is synthesized by many cell types upon appropriate stimulation and which can act on many cell types during several disease states such as inflammation and cancer [1]
IL-6 knock-out mice are protected from development of experimental autoimmune encephalomyelitis (EAE), the mouse model of human multiple sclerosis [56,57,58] and mouse models of rheumatoid arthritis [59,60]
It was shown in the same study that deletion of STAT3 in the intestinal epithelium led to more severe dextran sulfate sodium (DSS) colitis with pronounced colonic ulcerations and body weight loss, indicating that the IL-6 response in the intestinal epithelial cells was important for regeneration [110]
Summary
IL-6 is a four-helical cytokine with pleiotropic activities, which is synthesized by many cell types upon appropriate stimulation and which can act on many cell types during several disease states such as inflammation and cancer [1]. Since on most cells gp130 is expressed at higher levels than IL-6R, stimulation by IL-6 leads to the stimulation of only some gp130 molecules whereas stimulation with the IL-6/sIL-6R complex leads to the activation and stimulation of all gp130 proteins resulting in a higher signal amplitude as a consequence of IL-6 trans-signaling as compared with IL-6 signaling via the membrane-bound IL-6R. This resulted in significantly longer stimulation mediated by the IL-6/sIL-6R complex as compared to IL-6 alone [17] This property of IL-6 trans-signaling might be important for several cellular or tissue responses, which can only be induced by IL-6 trans-signaling but not by IL-6 classic signaling via the membrane-bound IL-6R [18]. Cleavage of ligands of the EGF-R is needed for the systemic activity of the ligands and for the full stimulation of the EGF-R [47]
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