Recombinant Human TNF RI/TNFRSF1A Fc Chimera Protein

TNF receptor 1 (TNF RI; also called TNF R-p55/p60 and TNFRSF1A) is a 55 kDa type I transmembrane protein member of the TNF receptor superfamily, designated TNFRSF1A (1, 2). Human TNF RI is a 455 amino acid (aa) protein that contains a 21 aa signal sequence and 190 aa ECD with a PLAD (pre-ligand assembly domain) that mediates constitutive dimer/trimer formation, followed by four CRD (cysteine-rich domains), a 23 aa transmembrane domain, and a 221 aa cytoplasmic sequence that contains a neutral sphingomyelinase activation domain and a death domain (3, 4). The ECD of human TNF RI shows 70%, 69%, 80%, 80%, and 73% aa identity with mouse, rat, canine, feline and porcine TNF RI, respectively; and it shows 23% aa identity with the ECD of TNF RII. Both TNF RI and TNF RII (TNFRSF1B) are widely expressed and contain four TNF-alpha trimer-binding CRD in their ECD. However, TNF RI is thought to mediate most of the cellular effects of TNF-alpha (3). It is essential for proper development of lymph node germinal centers and Peyer’s patches, and for combating intracellular pathogens such as Listeria (1, 2, 5). TNF RI is also a receptor for TNF-beta /TNFSF1B (lymphotoxin-alpha) (6). TNF RI is stored in the Golgi and translocates to the cell surface following pro‑inflammatory stimuli (7). TNF-alpha stabilizes TNF RI and induces its sequestering in lipid rafts, where it activates NF kappaB and is cleaved by ADAM-17/TACE (8, 9, 16). Release of the 28-34 kDa TNF RI ECD also occurs constitutively and in response to products of pathogens such as LPS, CpG DNA or S. aureus protein A (1, 10-12). Full-length TNF RI may also be released in exosome-like vesicles (13). Release helps to resolve inflammatory reactions, since it down-regulates cell surface TNF RI and provides soluble TNF RI to bind TNF-alpha (10, 14, 15). Exclusion from lipid rafts causes endocytosis of TNF RI complexes and induces apoptosis (1). Mutations of human TNF R1 can result in inflammatory episodes known as TRAPS (TNFR-associated periodic syndrome) (7).