Alt. symbols: IL1RA | ICIL-1RA | IL1F3 | IRAP | IL-1RN | MGC10430

Approved name: interleukin 1 receptor antagonist
Alt. names: interleukin-1 receptor antagonist protein, intracellular interleukin-1 receptor antagonist

Location: 2q14.1: 113099315 - 113134016 (+)
Gene type: protein_coding, 14 transcripts.

Scores: LoFtool: 0.375000 | pLI: 0.34021895 | LOEUF: 0.907

HGNC: 6000

NCBI: 3557, RefSeq: NG_021240.1

Ensembl: ENSG00000136689.20

LRG_188 | Status: public

OMIM: 147679

Expression | ProteinAtlas

IL1RN encodes IL1 receptor antagonist (IL-1Ra), a protein that can occupy the binding pocket of IL-1R1 to prevent its association with co-receptor IL1RAP without eliciting any downstream signaling (PMID: 31281320). IL-1Ra can also bind IL-1R1 with equal affinity as IL-1beta, thus it can also directly compete with ligands IL-1alpha and IL-1beta for binding. Through these mechanisms, IL1Ra can neutralizing downstream inflammatory responses engendered by IL-1 signaling. IL-1Ra was the first naturally-occurring specific receptor antagonist to be described.

Generalized pustular psoriasis (GPP) is an extremely rare type of psoriasis, presenting with pus-filled blisters covering the entire body and often associated with systemic inflammation (PMID: 35060076). Neutrophils isolated from patients with GPP induce greater upregulation of inflammatory cytokines (IL-1β, IL-36G, IL-18, TNF-α) and chemokines in keratinocytes than those from patients without GPP. These neutrophils are then rapidly internalized by keratinocytes, which further amplifie s expression of these inflammatory molecules by activating NF-κB and MAPK signaling (PMID: 30811955). Three monogenic SAIDs are characterized by GPP featuring keratinocyte inflammation: DIRA (IL-1 receptor antagonist deficiency) [OMIM: 612852] due to mutations in IL1RN encoding the IL-1 receptor antagonist (IL-1Ra), DITRA (IL-36 receptor antagonist deficiency) [OMIM: 614204] due to mutations in IL36RN encoding IL-36 receptor antagonist (IL-36Ra), and CAMPS (CARD14-mediated psoriasis). In general, DIRA usually presents with more significant signs of systemic inflammation than DITRA or CAMPS. Emerging evidence also suggests that variants in the different GPP-associated genes may interact in complex digenic or oligogenic combinations to engender or modify disease (PMID: 28887889, 31062396). Biallelic nonsense mutations, as well as large and small deletions, in IL1RN lead to the production of absent or defective IL-1Ra, allowing the unopposed action of pro-inflammatory cytokines IL-1alpha and IL-1beta. This results in DIRA, a condition characterized by life-threatening systemic inflammation with skin and bone involvement manifesting as early-onset pustular dermatitis, multifocal osteomyelitis, periostitis and nail changes. Less frequently reported manifestations include interstitial lung disease, atlantoaxial subluxation due to odontoid destruction and CNS vasculitis (PMID: 23711932). Consistent with this mechanism, patients respond well to anakinra or rilonacept, which leads to rapid resolution of symptoms, normalizes acute phase reactants and prevents the recurrence of skin and bone manifestations. Fevers are absent or low-grade, but patients show markedly elevated inflammatory markers. IL-1β stimulation of patient PBMCs leads to significant over-production of IL-1alpha, MIP-1alpha, TNF-alpha, IL-8, and IL-6 relative to controls and increased IL-17-secreting cells are seen on patients’ skin biopsies. Histological findings on the skin biopsy include corneal pustules, acanthosis and hyperkeratosis, while radiographic manifestations include widened ribs and clavicles, and multifocal osteolytic lesions mainly affecting the long bones (PMID: 23711932). Some populations have quite high allele frequencies of IL1RN mutations, possibly due to founder effects and/or population bottlenecks (i.e. Puerto Rican, Indian, Dutch, Newfoundlander, Brazilian) (PMID: 19494218, 22127713, 28503715). For example, the 2-bp deletion has an allele frequency of 0.2% in Newfoundland and the 175-kb deletion has an allele frequency of 1.3% northwestern Puerto Rico. Moreover, the incidence of DIRA in some parts of Puerto Rico may be as high as 1 in 6,300 births (PMID: 19494218). [Load More]