IL1ra

Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring anti-inflammatory protein that binds to the interleukin-1 receptor type I (IL-1RI) with high affinity, blocking signaling by the pro-inflammatory cytokines IL-1 alpha and IL-1 beta. It is encoded by the IL1RN gene in humans and is produced by various cell types, including monocytes, macrophages, neutrophils, epithelial cells, and synovial fibroblasts. IL-1Ra expression rises in response to inflammatory stimuli as part of a negative feedback mechanism to limit IL-1–driven effects.

Mechanistically, IL-1Ra competes with IL-1 for IL-1RI binding but does not trigger downstream signaling. By occupying the receptor without initiating signal transduction, it prevents activation of NF-κB and MAPK pathways and reduces transcription of pro-inflammatory genes.

(endogenous forms) The IL1RN gene yields a canonical secreted IL-1Ra protein, roughly 17 kDa in size, that contains a signal peptide for secretion. In addition, several intracellular isoforms (icIL-1Ra) arise from alternative splicing and lack signal peptides, contributing to intracellular regulatory functions.

Therapeutic use and pharmacology: Recombinant human IL-1Ra, known as anakinra, is used clinically as an immunomodulatory drug. It is approved for rheumatoid arthritis, systemic juvenile idiopathic arthritis, adult-onset Still’s disease, and cryopyrin-associated periodic syndromes, among other autoinflammatory conditions. It is administered by subcutaneous injection, with dosing tailored to the condition and patient factors. Common adverse effects include injection-site reactions and an increased risk of infections; neutropenia is uncommon but possible. In renal impairment, dosing considerations may apply.

Genetic deficiency: Mutations in IL1RN cause deficiency of the IL-1 receptor antagonist (DIRA), a severe neonatal inflammatory syndrome that responds to IL-1 blockade.