Interleukin-6 receptor signaling. II. Bio-availability of interleukin-6 inserum

Interleukin-6 (IL-6) is used as a growth factor by various tumor cells. It binds to a gp80 specific receptor (IL-6R) and then to a gp130 transducing c hain. Both receptor chains are released as soluble functional proteins whic h circulate in biological fluids. With a view to studying the physiological role of these soluble receptors, both proteins were purified from human pl asma. Surface plasmon resonance was used to measure the kinetic constants o f equilibria between IL-6 and natural sIL-6R, and between the IL-6/sIL-6R c omplex and soluble gp130, Kd values were found to be 0.9 and 2.3 nM respect ively. Soluble natural IL-6R and gp130 were also found to interact with a K d of 2.8 nM in the absence of IL-6, By using these Kd values, a mathematica l simulation predicted that 1) within a Large range of IL-6, sIL-6R and sgp 130 concentrations, free IL-6 represents 30% of the total circulating cytok ine, 2) sIL-6R overconcentrations lead to dramatic changes of the concentra tion of free IL-6, 3) increased concentrations of sgp130 should produce an efficient buffering effect on the IL-6/sIL-6R complex without incidence on the level of free IL-6, According to this model, the IL-6/sIL-6R complex ap pears to be an important support of IL-6 signaling in the most commonly enc ountered in vivo situations. The concentration of this complex is directly under the control of the concentration of sIL-6R; its bioavailability shoul d be efficiently buffered by increased sgp130 concentrations.