>IL-6 / Interleukin 6 & Receptor
IL-6 / Interleukin 6 & Receptor
IL-6 / Interleukin 6
IL-6 / Interleukin 6, a type of interleukins, is a multifunctional cytokine that affects virtually every organ system, most notably the immune system. IL-6 / Interleukin 6 is a potent and essential factor for the normal development and function of both T and B lymphocytes1 and has broad actions on cells of the hematopoietic system. IL-6 / Interleukin 6 also up-regulates the multidrug resistance 1 (MDR-1) gene through activation of NF-IL6, which, in turn, transactivates the MDR-1 gene through a Y-box motif. IL-6 is also a central regulator of the acute-phase response in the liver and regulates fever. Human diseases that involve prolonged inflammation frequently exhibit cachexia and loss of muscle mass, and IL-6 appears to be the mediator of these processes as well.
Interleukin 6 Function
IL-6 may mediate loss of adipose tissue in part by enhancing endogenous corticosteroid secretion. It is noteworthy that high circulating levels of IL-6 also have been linked to insulin resistance, high body mass index, and obesity. Human adipose tissue expresses IL-6, and adipocytes in culture express IL-6 constitutively. IL-6 also exerts its effects on the central nervous system, where it is known that cytokines from the IL-6 family regulate glial cell activation. IL-6 is an important factor in many disease states including, rheumatoid arthritis, systemic-onset juvenile idiopathic arthritis, systemic lupus erythematosus, Crohn disease, inflammatory bowel disease, cardiovascular disease, sepsis, fever, cachexia, insulin resistance, osteoporosis, and many types of cancer. IL-6 also is observed at higher levels in the elderly, and it is believed that IL-6 contributes to some of the changes associated with advanced age, such as decreased lean body mass, low-grade anemia, lymphoproliferative disorders, multiple myeloma, osteoporosis, and Alzheimer disease. Individuals with these pathologies exhibit elevated serum IL-6 levels compared with the levels in normal controls.
IL-6 Family Ligand
IL-6 Family Receptor
IL-6 Family Signaling Related Molecules
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IL-6 Receptor and IL-6 Signaling
The IL-6 receptor (IL-6R) is a member of the Class I cytokine receptor family. Functional Class I receptors contain high-affinity ligand-binding components and signal-transducing components, and are thus multichain receptor complexes that often share the signal-transducing component. There are 2 distinct components of the IL-6R. The ligand-binding portion of the IL-6R is an 80-kDa molecule that associates directly with IL-6. It exists in both a membrane-bound and a soluble form. The signal-transducing component of the IL-6R complex is glycoprotein 130 (gp130), sometimes called the IL-6Rβ chain. Gp130 alone is unable to bind IL-6, but plays an important role in the formation of high-affinity IL-6 binding sites and transduction of the IL-6 signal. IL-6 induces either a hexameric complex or a tetrameric complex.
All members of the IL-6 family of cytokines share the gp130 molecule as a critical component for signal transduction, which explains the functional redundancy of cytokines in the IL-6 family. A soluble form of the IL-6Rα chain was purified first from human urine. Soluble IL-6Rα (sIL-6Rα) binds to IL-6 and forms a circulating complex. This soluble complex then binds cells that express gp130 and induces signal transduction and gene expression in the recipient cell. These complexes may be very important proinflammatory mediators13 and can confer IL-6 responsiveness to cells that express gp130, but not to cells that express IL-6Rα alone. This process is referred to as trans-signaling. In addition to sIL-6Rα, soluble gp130 (sgp130) also exists in human serum and acts as an antagonist of the IL-6/sIL-6Rα complex.
A variety of events takes place downstream of gp130 activation by ligand, including activation of cytoplasmic tyrosine kinases and modification of transcription factors. Although gp130 has no intrinsic kinase domain, several investigators have shown that Janus kinase 1 (JAK1), JAK2, and tyrosine kinase 2 (TYK2) of the JAK family are associated constitutively with gp130 and are activated in response to IL-6 family members. Activation of these kinases, in turn, leads to tyrosine phosphorylation of the latent cytoplasmic transcription factors called signal transducers and activators of transcription (STATs). The main STAT activated by IL-6 and gp130 receptor complexes is STAT3. In addition to STAT3, the Ras protein also is activated in response to IL-6. After Ras activation, hyperphosphorylation of mitogen-activated protein kinase (MAPK) occurs as well as an increase in its serine/threonine kinase activity. MAPK then phosphorylates the NF-IL6 transcription factor (nuclear factor for IL-6) on serine 231 and threonine 235, a process that is essential for DNA binding. NF-IL6 has a basic leucine zipper motif and is a member of the C/EBP family of transcription factors. NF-IL6 binds and activates the promoter regions of various acute-phase protein genes in the liver. Thus, when IL-6 binds to a cell through IL-6Rα/gp130 complexes, a series of events takes place that leads to the activation of STATs and NF-IL6, switching on target genes.
- David S. et al. (2007) Interleukin-6 and its receptor in cancer. Cancer. 110(9): 1911-1928.
- Jean-Michel Dayer. et al. (2010) Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology (Oxford). 49(1): 15–24.
- Whiteley W. et al. (2009) Inflammatory markers and poor outcome after stroke: a prospective cohort study and systematic review of interleukin-6. PLoS Med. 6(9):e1000145.
- Zoran Culig. et al. (2012) Interleukin-6: A multifunctional targetable cytokine in human prostate cancer. Mol Cell Endocrinol. 360(1-2): 52–58.
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