Interleukin-6 trans-signalling in chronic inflammation and cancer.
Interleukin-6 (IL-6) is a cytokine, which plays an important role in many chronic inflammatory diseases. IL-6 belongs to a family of 10 cytokines, which all act via receptor complexes containing the cytokine receptor subunit gp130. On cells, IL-6 first binds to a specific membrane-bound IL-6R and the complex of IL-6 and IL-6R interacts with gp130 leading to signal initiation. Whereas gp130 is widely expressed throughout the body, the IL-6R is only found on some cells including hepatocytes and some leucocytes. A soluble form of the IL-6R is an agonist capable of transmitting signals through interaction with the gp130 protein. In vivo, the IL-6/soluble IL-6R complex stimulates several types of target cells, which are unresponsive to IL-6 alone, as they do not express the membrane-bound IL-6R. We have named this process trans-signalling. We provided evidence that a soluble form of the IL-6 family signalling receptor subunit gp130 is the natural inhibitor of IL-6 trans-signalling responses. We showed that in chronic inflammatory diseases such as inflammatory bowel disease, peritonitis, rheumatoid arthritis, asthma as well as in colon cancer, IL-6 trans-signalling is critically involved in the maintenance of the disease state. Moreover, in all these animal models, the progression of the disease can be interrupted by specifically interfering with IL-6 trans-signalling using recombinant-soluble gp130Fc protein. The pathophysiologic mechanisms by which the IL-6/soluble IL-6R complex perpetuates the inflammatory state are discussed.
Scheller
J
J
Biochemisches Institut, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
Ohnesorge
N
N
Rose-John
S
S
D000818:Animals; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D003110:Colonic Neoplasms / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D012995:Solubility
D015850:Interleukin-6; D019947:Receptors, Interleukin-6