Curcumin induces IL-6 receptor shedding via the ADAM10 proteinase

Proteolytic cleavage and release of single-spanning transmembrane receptors, a process called shedding, is vital for normal physiological functions and pathological responses, including inflammation and cancer. Interleukin-6 receptor (IL-6R) is one of the principal single-spanning transmembrane receptors expressed in hepatocytes and subpopulations of leukocytes, including monocytes and macrophages. Soluble IL-6R (sIL-6R) is also present in human plasma. Herein, we report that membrane-modulating agents including curcumin, enhance IL-6R shedding in human monocytes via a mechanism involving a disintegrin and metalloprotease 10 (ADAM10). Furthermore, amphiphilic derivatives of turmeric curcuminoids increased sIL-6R levels in culture supernatants and altered the membrane domains formed on giant vesicles. These findings offer insights into the mechanism underlying the induction of ectodomain cleavage of IL-6R and ascertain the function of liberated sIL-6R. They can provide a novel strategy to develop therapeutic intervention using membrane-active compounds, such as curcuminoids, for diseases such as inflammation and cancer.