title: IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6.
abstract: Interleukin-6 (IL-6) is a cytokine with many activities. It has functions in the regulation of the immune system and the nervous system. Furthermore, IL-6 is involved in liver regeneration and in the metabolic control of the body. On target cells, IL-6 binds to an 80 kDa IL-6 receptor (IL-6R). The complex of IL-6 and IL-6R associates with a second protein, gp130, which thereupon dimerizes and initiates intracellular signaling. Whereas gp130 is expressed on all cells, IL-6R is only present on few cells in the body including hepatocytes and some leukocytes. Cells, which do not express IL-6R cannot respond to the cytokine, since gp130 alone has no measurable affinity for IL-6. Interestingly, a soluble form of IL-6R (sIL-6R) comprising the extracellular portion of the receptor can bind IL-6 with a similar affinity as the membrane bound IL-6R. The complex of IL-6 and sIL-6R can bind to gp130 on cells, which do not express the IL-6R, and which are unresponsive to IL-6. This process has been called trans-signaling. Here I will review published evidence that IL-6 trans-signaling is pro-inflammatory whereas classic IL-6 signaling via the membrane bound IL-6R is needed for regenerative or anti-inflammatory activities of the cytokine. Furthermore, the detailed knowledge of IL-6 biology has important consequences for therapeutic strategies aimed at the blockade of the cytokine IL-6.
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany. rosejohn@biochem.uni-kiel.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
mesh_terms: D000818:Animals; D050822:Cytokine Receptor gp130 / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D019947:Receptors, Interleukin-6 / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D012995:Solubility
chemical_list: D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130
keywords: IL-6; IL-6 receptor; inflammation; inflammation associated cancer.; shedding; soluble receptor