Interleukin-1 Receptor Antagonist (IL-1RA)

Interleukin 1 receptor antagonist (IL-1RA) is a protein related to the IL-1 family based on its similarities in amino acid sequence to both IL-1 beta and IL-1 alpha, similarities in gene structure, and collective gene localization. The human gene contains four exons and maps to chromosome 2q13–14. IL-1 induces the release of prostaglandins, nitric oxide and the synthesis of chemokines that promote cells of the immune system to the site of infection. IL-1 RA binds to the IL-1 receptor and blocks IL-1 action through competitive inhibition. In contrast to IL-1, the binding of IL-1RA does not initiate signaling events. The secretion of IL-1 RA is mediated by a classical signal sequence while neither IL-1α nor IL-1β possess such a sequence. The lack of homology between IL-1 RA and IL-1 alpha or IL-1 beta near the N terminus may provide an explanation for the biosynthetic and functional differences between IL-1 RA and the two IL-1 proteins. The production of IL-1RA is stimulated by many substances including adherent IgG, cytokines, and bacterial or viral components. Triggering IL-1 production through cytokines like IL-13, IL-6, IL-4, IFNγ, GM-CSF and TGFβ apparently triggers IL-1RA synthesis. A number of cell types express IL-1RA, including monocytes, macrophages, neutrophils, Sertoli cells, hepatocytes, adipocytes, synovial fibroblasts, mast cells, pancreatic cells and intestinal epithelial cells. IL-1RA is an important natural anti-inflammatory protein that when missing or just available in inadequate amounts plays a key role in several pathological conditions such as rheumatoid arthritis, colitis, osteomyelitis, periostitis and pustulosis. A polymorphism of the IL –1RA gene is reported to be associated with increased risk of osteoporotic fractures and gastric cancer. In healthy tissue sufficient IL-1RA is produced to hold interleukin-1-mediated inflammation at bay. In cases of uncontrolled inflammation, there is an insufficient amount of IL-1RA to regulate the activity of interleukin-1.