IL1RN (Interleukin-1 Receptor Antagonist) encodes the IL-1 receptor antagonist (IL-1Ra), a naturally occurring 152-amino acid secreted glycoprotein. IL-1Ra competitively binds to the IL-1 receptor type I (IL-1R1) without triggering signal transduction, thereby blocking the pro-inflammatory actions of IL-1α and IL-1β. This makes IL-1Ra a crucial endogenous anti-inflammatory protein that regulates the magnitude and duration of IL-1-mediated inflammatory responses. Therapeutic recombinant IL-1Ra (Anakinra) is FDA-approved for rheumatoid arthritis and cryopyrin-associated periodic syndromes (CAPS) and is under investigation for neurodegenerative diseases [@arend1998][@basu2007].
IL1RN (Interleukin-1 Receptor Antagonist) encodes the IL-1 receptor antagonist (IL-1Ra), a naturally occurring 152-amino acid secreted glycoprotein. IL-1Ra competitively binds to the IL-1 receptor type I (IL-1R1) without triggering signal transduction, thereby blocking the pro-inflammatory actions of IL-1α and IL-1β. This makes IL-1Ra a crucial endogenous anti-inflammatory protein that regulates the magnitude and duration of IL-1-mediated inflammatory responses. Therapeutic recombinant IL-1Ra (Anakinra) is FDA-approved for rheumatoid arthritis and cryopyrin-associated periodic syndromes (CAPS) and is under investigation for neurodegenerative diseases [@arend1998][@basu2007].
Molecular Function
IL-1 Receptor Antagonism
IL-1Ra functions as a competitive antagonist at the IL-1 receptor:
Receptor binding: IL-1Ra binds IL-1R1 with similar affinity to IL-1α and IL-1β, but without activating downstream signaling
No signaling: The IL-1Ra/IL-1R1 complex cannot recruit the IL-1 receptor accessory protein (IL-1RAP), blocking signal transduction
Four isoforms: Generated by alternative splicing — a secreted form (sIL-1Ra) and three intracellular forms (icIL-1Ra1, icIL-1Ra2, icIL-1Ra3)
Expression regulation: Low basal expression in most tissues; strongly upregulated by IL-1β, TNF-α, and TLR ligands
Reduces neuronal death: In mouse models of AD, IL-1Ra administration reduces hippocampal neuron loss and improves cognitive performance
Genetic evidence: IL1RN polymorphisms have been associated with AD risk in some populations [@wu2018][@andrer2005]
Parkinson's Disease
In [Parkinson's Disease](/diseases/parkinsons-disease), IL-1Ra provides neuroprotection to dopaminergic neurons:
Nigral protection: IL-1Ra administration in the 6-OHDA and MPTP models protects [substantia nigra](/brain-regions/substantia-nigra) dopaminergic neurons from degeneration
Microglial suppression: Reduces IL-1β-mediated microglial activation and oxidative stress in the nigrostriatal pathway
Motor improvement: IL-1Ra treatment improves behavioral outcomes in PD animal models [@depino2015][@mccoy2012]
Stroke and Ischemia
IL-1Ra has been extensively studied in cerebral ischemia:
Neuroprotection: IL-1Ra reduces infarct volume and improves functional outcomes in transient and permanent middle cerebral artery occlusion (MCAO) models
Anti-inflammatory: Blocks IL-1β-mediated recruitment of leukocytes to ischemic brain tissue
Clinical translation: A Phase II trial of intravenous IL-1Ra in acute ischemic stroke showed good safety and promising efficacy signals
BBB penetration: IL-1Ra crosses the [blood-brain barrier](/entities/blood-brain-barrier) in sufficient quantities to exert CNS effects [@clarke2018]
Traumatic Brain Injury
Secondary damage reduction: IL-1Ra reduces inflammation-driven secondary injury following TBI
Motor recovery: Improves motor function recovery in TBI models
Clinical trial: Ongoing Phase II studies with Anakinra in moderate-severe TBI