sIL6R

sIL6R, or soluble interleukin-6 receptor, is a circulating form of the IL-6 receptor that can bind the cytokine interleukin-6 (IL-6). It is generated mainly by proteolytic shedding of the membrane-bound IL-6 receptor (mIL-6R) from cell surfaces, a process mediated by metalloproteases such as ADAM10 and ADAM17. A minority of sIL-6R may arise from alternative splicing of IL6R mRNA. The soluble receptor circulates in blood and other body fluids and can participate in IL-6 signaling beyond cells that naturally express mIL-6R.

Mechanistically, when sIL-6R binds IL-6, the resulting IL-6/sIL6R complex can engage gp130, which is broadly expressed on many cell types that lack mIL-6R. This enables a signaling mode known as trans-signaling, triggering downstream pathways such as JAK/STAT3, MAPK, and PI3K in cells previously unresponsive to classic IL-6 signaling. Because gp130 is widely distributed, trans-signaling widens the range of IL-6–responsive tissues. Classic signaling, in contrast, occurs when IL-6 binds mIL-6R on cells that express it.

Regulation and implications of sIL6R activity are context dependent. The naturally occurring soluble glycoprotein sgp130 can bind IL-6/sIL6R complexes and selectively inhibit trans-signaling. This has spurred the development of targeted therapies, such as sgp130Fc, to block trans-signaling while preserving classical IL-6 signaling. Clinically, sIL6R levels can be elevated in various inflammatory and metabolic diseases and are studied as potential biomarkers, though interpretations vary by condition. Treatments like tocilizumab, which blocks IL-6R, affect both membrane and soluble forms.