Recombinant Human IL-12 R beta 2 Fc Chimera Protein, CF

The high-affinity IL-12 receptor complex includes the 100 kDa IL-12 receptor beta1 (IL-12 R beta1) and the 130 kDa IL-12 Receptor beta2 (IL-12 R beta2) subunits, both type I transmembrane proteins within the cytokine receptor superfamily (1, 2). Its ligand, IL-12, is a disulfide-linked dimer of 35 kDa (IL-12 alpha p35) and 40 kDa (IL-12 beta p40) subunits. IL-12 R beta2 binds IL-12 alpha and signals through Jak2, while IL-12 R beta1 binds IL-12 beta and signals through Tyk2 (3). IL-12 R beta1 is also a subunit of the IL-23 receptor complex (3). The 874 amino acid (aa) human IL-12 R beta2 includes a 23 aa signal peptide, a 599 aa extracellular domain (ECD) with five fibronectin type III (Fn III) domains, 8 potential N-glycosylation sites, and a WSXWS motif, a 21 aa transmembrane domain and a 219 aa cytoplasmic region with a Box 1 motif and a tyrosine phosphorylation site that both mediate intracellular signaling (3). Human IL-12 R beta2 ECD shares 69%, 67%, 79%, 81% and 82% aa sequence identity with mouse, rat, canine, porcine and bovine IL-12 R beta2, respectively. Human and mouse IL-12 R beta2 do not bind cross-species IL-12 (2). A human alternatively spliced 659 aa form contains a shortened, altered cytoplasmic sequence (4). Unlike IL-12 R beta1, which is constitutive in T cells, NK cells and B cells, IL-12 R beta2 expression is more limited (2). IL-12 R beta2 is expressed following STAT1 activation by IFN-gamma, IL-27 and/or T cell receptor stimulation of naïve T cells, allowing IL-12 to promote Th1, but not Th2, differentiation (5-7). Among B cells, surface expression is limited to naïve germinal center and memory B cells, and myeloma cells (2). Deletion of mouse IL-12 R beta2 causes systemic overexpression of IL-6, accelerated maturation of thymocytes, deficient regulatory T cell maturation and function, and reduced splenic T cell apoptosis (2, 8-10). These mice are susceptible to autoimmune diseases such as experimental autoimmune encephalitis and spontaneous B cell malignancies
(2, 8-10). In humans, polymorphism of the IL-12 R beta2 gene is associated with systemic sclerosis (11).