Insights from Interleukin-6 trans-signaling and implications for the control of cytokine activity

Interleukin-6 is a protein of 184 amino acids and belongs to the four-helical family of cytokines. Interleukin-6 is a major inflammatory mediator and an important target in the treatment of autoimmune diseases. In addition, Interleukin-6 has regenerative and protective functions in many organs such as the liver, the intestine and the central nervous system. Interleukin-6 binds to the Interleukin-6 receptor and this complex associates with the signaling receptor subunit gp130 to initiate intracellular signaling. The Interleukin-6 receptor occurs in membrane-bound and soluble form. Recent work has demonstrated that the house-keeping functions of Interleukin-6 are mediated via the membrane-bound Interleukin-6 receptor whereas the pro-inflammatory activities are brought about via the soluble Interleukin-6 receptor. Here, the biology of the Interleukin-6 receptor and consequences of blockade of Interleukin-6 activity are reviewed. Furthermore, it is speculated that soluble cytokine receptors might play an important role in the biology of other cytokines.