The inhibitor Dasatinib IL 6 receptor is activated through two separate, but related pathways, classical and trans signaling. Clas sical IL 6 receptor activation is facilitated through the IL 6 ligand binding to its membrane bound receptor. The receptor consists of two subunits, the IL 6 receptor alpha chain, which binds IL 6, and the transmembrane signaling subunit, glycoprotein 130, which is the intra cellular signal transducer and is ubiquitously expressed. Both IL 6R and gp130 are cleaved immediately before the membrane spanning region by alternative spli cing or shed by proteolytic enzymes to produce a soluble receptor located in extra cellular matrix. It is important Inhibitors,Modulators,Libraries to note that the expression Inhibitors,Modulators,Libraries pattern of IL 6R is limited to few cells of the immune system and conservatively dis persed among other cell types, meaning classical signal ing is highly conserved.

In contrast, gp130 is ubiquitously expressed. The basis of trans signaling is soluble IL 6R binding to IL 6 in the extra cellular matrix to form a Inhibitors,Modulators,Libraries IL 6 sIL 6R complex, which has an increased binding affinity to membrane bound gp130 subunits, resulting in the capability of IL 6 production in any cell type that expresses gp130. Upon binding through either the classical or trans sig nal, gp130 dimerizes and autophosphorylates, resulting in the activation of Janus kinase 1 and 2. These tyrosine kinases phosphorylate the cytoplasmic region of gp130 creating recruitment sites for signal transducer and activation of transcription 3, a Src homology 2 domain containing signaling molecule.

Activated STAT3 forms a dimer, autopho sphorylates, and translocates to the nucleus where it binds to enhancer elements of the IL 6 promoter region. Thus the main consequence of both classical or trans signal IL 6 receptor action is Inhibitors,Modulators,Libraries to induce gene transcrip tion and subsequent synthesis and secretion of IL 6, though trans signaling allows this in many more cell types, due to the ubiquitous Inhibitors,Modulators,Libraries expression of gp130. sIL 6R and soluble gp130 have varying effects on circulating IL 6. Where sIL 6R acts as an agonist, sgp130 acts as a partial antagonist, or decoy receptor, by binding IL 6 or the IL 6 sIL 6R complex and prevents the binding of membrane bound gp130 and further sig nal transduction. The action of IL 6 is heavily dependent on the loca tion of the receptors and the cell types exposed to the cytokine.

For instance, IL 6 binding to IL 6R located on T cells leads to the differentiation of stem line T cells to helper T cells whereas in the gastro intestinal tract, IL 6 and its receptors on epithelial cells contribute to peripheral disorders such as colitis and Crohns disease. However, studies selleckchem examining IL 6 receptor signaling or trans signaling in the CNS are limited and we are aware of no studies examining the extent to which IL 6 receptor signaling affects neuroinflammation and infec tion related changes in behavior.