IL1 receptors

Two distinct IL-1 receptors have been identified as shown by the cloning studies of Sims and coworkers. Both receptors are members of the immunoglobulin superfamily. The type I receptor is an 80 kDa transmembrane protein, 552 amino acids long, with a single 22 amino acid transmembrane region and a long cytoplasmic tail of 213 amion acids. Its extracellular ligand-binding region consists of three immunoglob-ulin-like domains. The type II receptor is a 60 kDa protein and is similar to the type I receptor in its extracellular and transmembrane regions. The type II receptor has a short cytoplasmic tail of 29 amino acids and is incapable of signal transduction. The type II receptor actually competitively inhibits IL-1 activity by acting as a 'decoy' receptor for IL-1, and regulates the level of extracellular IL-1.

IL-1 acts on target cells by binding with high affinity (Kd of 10~10 m) to IL-1 type I receptors. Type I receptors are found on T cells, endothelial cells, hepatocytes, fibroblasts and keratinocytes, whereas type II receptors appear to have a more restricted distribution. Type II IL-1 receptors are the predominant receptor on B cells, monocytes and neutrophils. IL-lct, IL-1 £ and IL-lra show detectable affinity for both types of IL-1 receptors. However, IL-la binds preferentially with somewhat higher affinity to type I receptor and IL-1 (3 binds preferentially to type II receptor. IL-lra binds type I receptor with considerably higher affinity than it binds to type II 'decoy' receptor, and it can block the binding to type I receptor and consequent biological activities of both IL-la and IL-1 p. However, a 10- to 500-fold excess of IL-lra may be necessary to achieve a 50% inhibition of the biological effects of IL-1 in vitro. Pro-IL-l(3 does not bind to type I receptor and therefore has no detectable biological activity. The receptor binding affinity and biological activities of the pro and mature forms of IL-la appear indistinguishable. Despite the low number of type I receptors (200 per cell), all biological responses of IL-1 are mediated by type I receptors. A receptor occupancy of less than 5% per cell is sufficient to activate cells. These data suggest that a major amplification of IL-1 signal must occur after IL-1 ligand/receptor interaction. Recently, Greenfeder and colleagues identified an IL-1 receptor accessory protein which is the putative signal transducing subunit of the IL-1 receptor complex. IL-1 receptor accessory protein does not bind IL-1 directly but forms a complex with type I IL-1 receptor after it is bound by either IL-la or IL-1(3 but not IL-lra.

Expression of both type I and type II IL-1 receptors is regulated to control inflammation and immune responses. Dexamethasone, PGE2 and cytokines with known anti-inflammatory properties, such as IL-4, IL-10, IL-13 and TGF|3, can increase receptor expression and shedding from cell membrane. The extracellular domain of both type I and type II receptor is shed by activated neutrophils and monocytes and the solubilized shed receptor binds and inhibits IL-1 p functions. Recently, it was shown that vaccinia and cowpox viruses encode a protein with 30% sequence homology to the soluble type II IL-1 receptor. The presence of this protein counteracts the host inflammatory response to these viruses because viruses genetically engineered to lack these genes become less pathogenic.

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