In this video, we will discuss the unique dual-signaling mechanism of interleukin-6, or IL-6, which enables it to affect many cell types and cause chronic inflammation and the clinical manifestations of rheumatoid arthritis, or RA.
Unlike most cytokines, the dual-signaling mechanism of IL-6 includes cis-signaling and trans-signaling.
Cis-, or classical signaling, utilizes membrane-bound receptors that are present on a limited number of cells, including hepatocytes and leukocytes (for example, neutrophils, monocytes, macrophages, and some lymphocytes). Cis-signaling is important for anti-inflammatory, homeostatic, and protective functions.
Trans-signaling uses a soluble IL-6 receptor to interact with many additional cells that do not have membrane-bound receptors, such as osteoclasts, fibroblast-like synoviocytes, endothelial cells, adipocytes, and neural cells. This is the predominant IL-6 signaling mechanism observed in inflammatory disease states such as RA.
A key piece of IL-6 signaling- both cis and trans – is the ubiquitously expressed signal-transducing gp130. It is important to note that gp130 is used in the signaling of many other groups of cytokines, such as IL-11 and IL-27.
The complex of IL-6 and its receptor must engage gp130. Alone, IL-6 binding to its receptors will not adequately initiate signaling. When the membrane-bound or the soluble IL-6 receptor/IL-6 complex binds to gp130, homodimerization is induced. This conformational change activates a pair of JAK proteins, which then phosphorylate each other through a process referred to as autophosphorylation. Then they phosphorylate the cytoplasmic tail of the gp130 receptor and initiate downstream signaling.
There are three distinct downstream signaling pathways of IL-6: The JAK/STAT pathway, MAP-kinase pathway, and PI3-kinase pathway. All 3 pathways are critical to IL-6 intracellular signaling in RA that ultimately mediates downstream effects indicative of RA.
The dual signaling of IL-6 allows it to affect almost every cell type, organ, and tissue. Elevated IL-6 levels affect: Hepatocytes, which can contribute to the acute-phase response, restrict the supply of iron to hemoglobin synthesis, and cause metabolic dysregulation. Osteoclasts and fibroblast-like synoviocytes, which leads to bone resorption. Neural and glial cells, which leads to fatigue, pain, altered sleep, morning stiffness, and affects mood. Endothelial cells, which leads to cardiovascular effects. Adipocytes, which leads to metabolic dysregulation.
In summary, cis- and trans-signaling of IL-6 explains its pleiotropic nature; that is, its ability to affect almost all cell types, organs, and tissues.
To find out more about IL-6, please browse additional videos in this series on RAandIL6.com. This video was brought to you by Sanofi Genzyme and Regeneron Pharmaceuticals.