il-18

IL-18 (Interleukin-18)

IL-18 is a pro-inflammatory cytokine of the IL-1 family that drives interferon-gamma (IFN-γ) production from T cells and NK cells, particularly in synergy with IL-12. It is produced as an inactive 24-kDa precursor (pro-IL-18) and activated by caspase-1 (canonical nlrp3-inflammasome output) and by caspase-4/5 (non-canonical pathway). Release occurs through gasdermin-D pores during pyroptosis. Endogenous inhibition is provided by IL-18BP (IL-18 binding protein). In aging, serum IL-18 is chronically elevated and has been linked to age-related macular degeneration and cardiovascular inflammation; it is the second major cytokine output of the NLRP3 inflammasome alongside il-1b.

Identity

• UniProt: Q14116 (IL18_HUMAN), Swiss-Prot (manually curated)
• NCBI Gene: 3606
• HGNC: 5986; symbol IL18
• Ensembl: ENSG00000150782
• Mouse ortholog: Il18 (one-to-one)
• Synonyms: IGIF (interferon-gamma-inducing factor), IL-1F4, interleukin-1 gamma
• Length: 193 amino acids (canonical isoform); processed to mature ~156-aa active form after caspase cleavage

Domain structure and processing

IL-18 adopts a beta-trefoil fold (14 β-strands, 3 helices, 3 turn regions; residues 23–191), shared across IL-1 family members ¹. The precursor form (24 kDa pro-IL-18) is constitutively expressed in the cytosol of macrophages, dendritic cells, epithelial cells, and hepatocytes. It lacks a signal peptide and is not secreted via the classical ER-Golgi route.

Proteolytic activation:

• Caspase-1 cleaves at Asp35/Asn36 (canonical; nlrp3-inflammasome- and NLRC4-inflammasome-dependent) → active ~18-kDa mature form ²³
• Caspase-4 / caspase-5 — non-canonical inflammasome cleavage; exact sites partially overlapping needs-replication
• Caspase-3 cleaves at Asp69/Ile70 — inactivates IL-18 (anti-inflammatory cut; yields ~14-kDa product with no IFN-γ–inducing activity); distinct from caspase-1 site ³

Secretion: Active IL-18 is released through gasdermin-D pores during pyroptosis, or in GSDMD-independent but caspase-1-dependent vesicular secretion. One O-linked glycosylation site is documented (UniProt Q14116).

An alternative splice isoform (Delta3pro-IL-18, isoform 2) is expressed in ovarian carcinoma but not normal ovarian epithelium; it is resistant to caspase-1 activation — aging relevance is unclear.

Signaling: IL-18Rα / IL-18Rβ complex

Active IL-18 signals through a heterodimeric receptor complex ⁴:

1. IL-18Rα (IL18R1) — low-affinity ligand-binding subunit
2. IL-18Rβ (IL18RAP) — signaling co-receptor; required for high-affinity binding and signal transduction

Receptor assembly activates MyD88 → IRAK → TRAF6 → TAK1 → NF-κB (and AP-1), driving transcription of IFN-γ, GM-CSF, IL-8/CXCL8, and additional pro-inflammatory genes. The pathway is structurally parallel to IL-1R/TLR signaling.

IL-12 synergy: IL-18 alone is a weak IFN-γ inducer; in combination with IL-12, it potently drives Th1 polarization, NK cell activation, and IFN-γ burst ⁵. This synergy is the canonical role for which IL-18 was originally named IGIF.

Endogenous antagonist: IL-18BP

IL-18 binding protein (IL-18BP) is a secreted protein that binds mature IL-18 with high affinity (Kd ~400 pM), neutralizing it before receptor engagement ¹. The most abundant splice variant (IL-18BPa) has a mature protein core of ~20 kDa (164 aa after cleavage of the 28-aa signal peptide); the fully glycosylated form runs at ~40 kDa on SDS-PAGE ⁶. IL-18BP is:

• A member of the immunoglobulin superfamily (not a receptor ectodomain — it is a distinct secreted protein)
• Constitutively expressed, especially in the spleen
• Encoded by poxviruses as a virulence factor (viral IL-18 decoy)
• The basis for tadekinig alfa (recombinant human IL-18BP; see Pharmacology below)

The IL-18 / IL-18BP molar ratio in serum is a better predictor of biological activity than IL-18 alone; in aging and inflammatory disease, free (unbound) IL-18 is elevated even when total IL-18 is only modestly increased. needs-replication — the free-IL-18 bioactivity index has not been prospectively validated as superior to total IL-18 for aging outcomes.

Role in aging and inflammaging

Serum elevation with age

Circulating IL-18 increases with chronological age across multiple observational cohorts. It is a component of the broader inflammaging signature alongside IL-6, TNF-α, and IL-1β ¹. Two primary mechanisms drive age-related IL-18 elevation:

1. NLRP3 priming + activation — accumulation of damage-associated molecular patterns (mitochondrial DNA, uric acid, cholesterol crystals) with aging provides both priming (NF-κB-dependent pro-IL-18 transcription) and activation signals for caspase-1
2. Reduced IL-18BP buffering capacity — less well characterized; possibly due to shifts in spleen/macrophage function with age no-mechanism

Age-related macular degeneration (AMD)

IL-18 and other inflammasome proteins are elevated in serum of AMD patients (IL-18 p=0.0009; AUC=0.73; n=27 AMD vs 61 controls); ASC protein levels explained ~19% of IL-18 variance (adjusted R²=0.1906), supporting direct inflammasome involvement ⁷. AMD is one of the most mechanistically-supported links between NLRP3/IL-18 and an age-associated disease. The drusen deposits in AMD activate the NLRP3 inflammasome in retinal pigment epithelium.

Dimension	Status
Pathway conserved in humans?	yes
Phenotype conserved in humans?	yes (AMD association shown in human cohorts)
Replicated in humans?	in-progress (mechanistic association; IL-18BP trials ongoing for inflammatory diseases)

Macrophage Activation Syndrome (MAS) / HLH

In adult-onset Still’s disease (AOSD) and NLRC4-mutation-driven MAS, serum IL-18 reaches extreme levels (sometimes >100,000 pg/mL vs. <1,000 pg/mL in healthy adults). These conditions are not aging per se but establish that IL-18 drives a cytokine storm phenotype directly relevant to hyperactivated inflammasome biology — the same mechanism proposed to underlie inflammaging at lower intensity ⁸.

Cardiovascular inflammation

IL-18 is elevated in coronary artery disease patients and correlates with inflammatory processes linked to aging, including shorter leukocyte telomere length in high-IL-18 individuals ⁹. needs-replication — prospective data linking IL-18 specifically (vs. the broader inflammatory milieu) to aging-related cardiovascular events in longitudinal cohorts is limited.

Pathway membership

• nlrp3-inflammasome — primary activation platform; caspase-1 produced within this complex cleaves pro-IL-18
• il-1-signaling — family-level signaling context; IL-18 shares MyD88/IRAK/NF-κB axis with IL-1
• interferon-gamma-pathway — upstream inducer of IFN-γ production in T cells and NK cells
• pyroptosis — IL-18 released through gasdermin-D pores during lytic cell death

Key interactors

• caspase-1 — primary protease; cleaves pro-IL-18 at Asp35/Asn36 to generate active form ²³
• gsdmd (gasdermin-D) — pore-forming protein that enables non-lytic and lytic IL-18 secretion
• asc — adaptor in NLRP3 inflammasome; required for caspase-1 recruitment and pro-IL-18 processing
• il-1b — co-produced cytokine; shares caspase-1 cleavage and gasdermin-D secretion mechanism; functional synergy in driving systemic inflammation
• interferon-gamma — primary downstream effector; IL-18 + IL-12 → strong IFN-γ induction from NK and T cells

Pharmacology

Tadekinig alfa (recombinant IL-18BP)

Tadekinig alfa is a recombinant human IL-18BP (rh-IL-18BP) developed by AB2 Bio Ltd. that neutralizes free IL-18 before receptor engagement.

Clinical development:

• Phase 2 (AOSD): 23 patients with active adult-onset Still’s disease; 80 or 160 mg SC three times weekly for 12 weeks; favorable safety profile and early signs of efficacy (approximately half of patients achieved response criteria by week 3) ⁸
• Phase 3 (NLRC4-MAS / XIAP deficiency): NCT03113760 — completed; indication is the rare monogenic form where IL-18 is the dominant driver
• Early Phase 1 (CAR T CRS/HLH): NCT05306080 — recruiting at University of Pennsylvania; positions IL-18BP as a rescue therapy for CAR T cell-related cytokine storm
• Druggability tier 1 per CLAUDE.md schema (a clinical-stage drug targeting the protein exists)

NLRP3 inhibitors (indirect)

Compounds that block the NLRP3 inflammasome upstream reduce caspase-1 activity and consequently IL-18 processing. Examples: MCC950 (CMPD-1), OLT1177 (dapansutrile). These are discussed on the nlrp3-inflammasome page.

No direct IL-18R antagonist approved

No anti-IL-18Rα monoclonal antibody has reached approval. The neutralization strategy via IL-18BP (tadekinig) is clinically favored over receptor blockade for IL-18.

Aging-context tier-1 rationale. Tadekinig alfa (recombinant human IL-18BP) reached Phase 3 for NLRC4-driven macrophage activation syndrome (MAS / XIAP deficiency) and Phase 2 for adult-onset Still’s disease — both rare monogenic / autoinflammatory indications, not aging-rejuvenation. The aging-context tier-1 designation reflects IL-18’s role as the second major NLRP3-inflammasome cytokine output (alongside IL-1β) and its established association with age-related macular degeneration, cardiovascular inflammation, and inflammaging. Strict Open Targets Approved Drug = true for an aging indication does not apply.

Footnotes

Limitations and knowledge gaps

• #gap/needs-gtex-lookup — GTEx aging correlation for IL18 transcript not yet populated
• #gap/needs-mr-study — Mendelian randomization of IL18 SNPs → aging outcomes not confirmed; mr-causal-evidence: not-tested until a formal IEU OpenGWAS lookup is run
• #gap/needs-human-replication — direct causal evidence that elevated IL-18 drives (rather than marks) inflammaging is lacking; observational data only in most aging cohorts
• #gap/needs-replication — free-IL-18 vs total-IL-18 as the relevant bioactivity index in aging not prospectively validated
• #gap/no-mechanism — mechanism(s) reducing IL-18BP buffering capacity with age not characterized
• #gap/needs-canonical-id — GenAge-human entry for IL18 not confirmed; lookup needed at genomics.senescence.info
• #gap/no-fulltext-access — Dinarello 2018 (doi:10.1111/imr.12621) and Opstad 2019 (doi:10.1016/j.exger.2019.01.020): DOI lookup failed despite green OA status; signaling pathway and cardiovascular/telomere claims sourced to these papers remain unverified against full text

See also

• il-1b — sibling cytokine; co-produced by NLRP3 inflammasome via caspase-1; canonical inflammasome output
• il-1a — sibling cytokine (co-seeded R25)
• il-1r1 — receptor for IL-1α/β; shares downstream signaling with IL-18R
• caspase-1 — processing enzyme; R24d
• nlrp3-inflammasome — primary activation platform; drafted R24d
• asc — inflammasome adaptor; R24d
• gsdmd — pore-forming executioner; R24d; enables IL-18 secretion
• pyroptosis — lytic cell-death program releasing IL-18; R24d process page
• chronic-inflammation — downstream hallmark driven by IL-18 signaling
• interferon-gamma — primary downstream effector cytokine

Footnotes

1. doi:10.1111/imr.12616 · Kaplanski G · Immunological Reviews 2018 · review · “Interleukin-18: Biological properties and role in disease pathogenesis” · 572 citations · IL-18BPa has exceptionally high affinity for IL-18 (Kd 400 pM); serum IL-18BP in healthy subjects 2000–4000 pg/mL vs IL-18 80–120 pg/mL (20-fold molar excess); IL-18 gene encodes 193-aa precursor synthesized as inactive 24-kDa precursor; caspase-1 N-terminus generated is 14 aa before the I-N-D consensus (placing cleavage ~Asp36 in human numbering) ↩ ↩² ↩³

2. doi:10.1038/386619a0 · Ghayur T et al. · Nature 1997 · n=N/A · in-vitro / in-vivo (mouse) · demonstrated caspase-1 (ICE) and caspase-4 process pro-IL-18; caspase-1 cleaves at predicted Asp35 site (D35A mutant blocks cleavage); caspase-1-deficient mice markedly reduced in serum IFN-γ (~5% of wild-type at 4–6 h post-LPS); specific caspase-1 inhibitor (Ac-YVAD-CHO) blocked both IL-1β and IFN-γ production from PBMCs with IC₅₀ = 2.3 ± 0.8 μM (IFN-γ) and 2.4 ± 0.8 μM (IL-1β) ↩ ↩²

3. doi:10.1126/science.275.5297.206 · Gu Y et al. · Science 1997 · n=N/A · in-vitro / in-vivo (ICE-/- mice) · ICE (caspase-1) cleaves pro-IL-18 at authentic site Asp35–Asn36 (kinetics: kcat/Km = 1.4 × 10⁷ M⁻¹ s⁻¹; Km = 0.6 ± 0.1 μM); CPP32 (caspase-3) cleaves at Asp69–Ile70 producing ~14-kDa fragment with no IFN-γ–inducing activity; ICE-/- Kupffer cells synthesize pro-IL-18 but fail to export mature IL-18; ICE-/- mice have reduced serum IGIF and IFN-γ after P. acnes + LPS challenge ↩ ↩² ↩³

4. doi:10.1111/imr.12621 · Dinarello CA · Immunological Reviews 2018 · review · “Overview of the IL-1 family in innate inflammation and acquired immunity” · DOI lookup failed (green OA, PMC mirror fetch failed); claims sourced to this footnote are unverified no-fulltext-access · ⚠️ Note: the originally supplied DOI 10.1002/eji.201746939 was found in the archive but title-matched a contact sensitizers / CD1 T-cell paper — DOI-title mismatch confirmed via ; corrected to 10.1111/imr.12621 (PMID 29247995) during seeding. ↩

5. doi:10.1038/378088a0 · Okamura H et al. · Nature 1995 · n=N/A · in-vitro / in-vivo (BALB/c mice) · original cloning of IGIF (later renamed IL-18); 192-aa precursor (murine); mature form 18–19 kDa by SDS-PAGE; demonstrated synergistic IFN-γ induction from T cells with IL-12; anti-IGIF antisera completely prevented LPS-induced liver injury in P. acnes-primed mice ↩

6. doi:10.1016/s1074-7613(00)80013-8 · Novick D et al. · Immunity 1999 · n=N/A · in-vitro / in-vivo (mouse) · IL-18BP purified from 500 L normal human urine on IL-18-agarose; ~40 kDa (glycosylated), ~20 kDa protein core on deglycosylation; most abundant human splice variant (IL-18BPa) encodes 28-aa signal peptide + 164-aa mature protein; IL-18BP abrogated circulating IFN-γ by >90% in LPS-challenged mice; belongs to Ig superfamily; identified poxvirus homologs (MCV ORF 54L, 47% identity); gene localized to chromosome 11q13 · ⚠️ Note: the originally supplied DOI 10.1016/s1074-7613(00)80009-5 was not found in the archive (DOI mismatch); corrected to 10.1016/s1074-7613(00)80013-8 during seeding via PubMed PMID 10023777 cross-check. ↩

7. doi:10.1167/tvst.9.13.27 · Weaver C, Cyr B, de Rivero Vaccari JC, de Rivero Vaccari JP · Translational Vision Science & Technology 2020 · observational · n=27–61 controls / 27–32 AMD patients (varies by analyte) · IL-18 significantly elevated in AMD serum (p=0.0009); AUC 0.73 for IL-18; adjusted R²=0.1906 (19% of IL-18 variance explained by ASC levels in linear regression); logistic regression identified ASC + HTN as AMD predictors ↩

8. doi:10.1136/annrheumdis-2017-212608 · Gabay C et al. · Annals of the Rheumatic Diseases 2018 · n=23 enrolled (10 in 80 mg group, 13 in 160 mg group) · open-label multicentre phase 2 dose-escalating · tadekinig alfa (80 or 160 mg SC three times weekly × 12 weeks) in adult-onset Still’s disease; favorable safety profile; 5/10 (50%) in 80 mg group and 6/12 (50%) in 160 mg group achieved predefined response criteria at week 3; 3 SAEs (one possibly related: toxic optic neuropathy); NCT02398435 ↩ ↩²

9. doi:10.1016/j.exger.2019.01.020 · Opstad TB, Arnesen H · Experimental Gerontology 2019 · observational · n=300 CAD patients · IL-18 levels associated with inflammatory processes; higher IL-18 in lower telomere-length quartile women · DOI lookup failed (green OA, fetch failed); claims sourced to this footnote are unverified no-fulltext-access ↩