IL-1 signaling pathway
The interleukin-1 (IL-1) signaling pathway is the principal mediator of sterile, innate-immune-driven inflammation in aged tissue. It transmits signals from two potent pro-inflammatory cytokines — IL-1β and IL-1α — through a shared receptor complex (IL-1R1 / IL-1RAcP) into the MyD88 → IRAK4 → TRAF6 → TAK1 → NF-κB / MAPK cascade. The pathway is tonically opposed by the endogenous antagonist IL-1Ra and the decoy receptor IL-1R2. Three FDA-approved biologics target this pathway, and the CANTOS trial (Ridker et al. 2017, n=10,061) established that pharmacological IL-1β blockade reduces cardiovascular events in humans, making this the most-validated therapeutic target within inflammaging 1.
This page is the integrating pathway page for the full IL-1 axis. Cytokine-specific biology lives on the atomic protein pages: il-1b, il-1a, il-1ra, il-1r1, il-18. Per-compound PK and trial data lives on canakinumab and the implicit stubs anakinra, rilonacept.
IL-1 family taxonomy
The IL-1 family currently has 11 members sharing structural homology (beta-trefoil fold) and, for most members, a shared receptor scaffold architecture 2 3:
| Cytokine | Gene | Receptor complex | Signal outcome | Notes |
|---|---|---|---|---|
| IL-1α | IL1A | IL-1R1 + IL-1RAcP | NF-κB / MAPK | Constitutive; alarmin; SASP apex regulator; also nuclear (intracrine) |
| IL-1β | IL1B | IL-1R1 + IL-1RAcP | NF-κB / MAPK | Requires inflammasome processing; primary pathological ligand in inflammaging |
| IL-1Ra | IL1RN | IL-1R1 (no IL-1RAcP) | None (pure antagonist) | Endogenous brake; basis of anakinra |
| IL-18 | IL18 | IL-18R1 + IL-18RAP | NF-κB / AP-1 → IFN-γ | Caspase-1 activated; NK/T-cell IFN-γ inducer |
| IL-33 | IL33 | ST2 (IL1RL1) + IL-1RAcP | NF-κB / MAPK | Alarmin; chromatin-associated; TH2 bias; senescence relevance emerging |
| IL-36α | IL36A | IL-36R + IL-1RAcP | NF-κB | Skin-dominant; weaker systemic aging role |
| IL-36β | IL36B | IL-36R + IL-1RAcP | NF-κB | Skin-dominant |
| IL-36γ | IL36G | IL-36R + IL-1RAcP | NF-κB | Skin-dominant |
| IL-36Ra | IL36RN | IL-36R (no IL-1RAcP) | None (antagonist) | Decoy for IL-36 axis |
| IL-37 | IL37 | IL-18Rα (complex) | Anti-inflammatory | Uniquely suppressive; attenuates innate responses |
| IL-38 | IL38 | IL-36R / IL-1RAPL2 | Anti-inflammatory | Relatively uncharacterised |
The aging-relevant members (bold) are IL-1α, IL-1β, IL-1Ra, and IL-18 — all of which have verified atomic pages in this wiki. IL-33 has emerging senescence relevance (released from senescent fibroblast nuclei upon lytic death) but is not yet seeded. needs-canonical-id — IL-33, IL-36 family, and IL-37 pages are implicit stubs.
Receptor architecture
IL-1R1 — the signalling receptor
IL-1R1 (UniProt P14778; gene IL1R1) is the primary signal-transducing receptor. It is a single-pass type I membrane glycoprotein with three extracellular Ig-like C2-type domains (D1–D3) for ligand binding and an intracellular TIR (Toll/IL-1 Receptor homology) domain for adaptor recruitment.
Ligand ranking for IL-1R1 binding affinity: IL-1β ≈ IL-1α >> IL-1Ra. Despite similar receptor affinity, IL-1Ra fails to recruit the co-receptor IL-1RAcP — this is the structural basis of its antagonism 4.
IL-1RAcP — the co-receptor
IL-1RAcP (IL-1 receptor accessory protein; gene IL1RAP; UniProt Q9NPH3) is the obligate co-receptor for IL-1R1 signalling. It is recruited to the IL-1R1·ligand complex and contributes its own TIR domain to form the two-TIR composite surface that recruits MyD88. IL-1RAcP is also the co-receptor for IL-33 (with ST2) and IL-36 signalling — making it a shared scaffold across three IL-1 family sub-axes.
IL-1R2 — the decoy receptor
IL-1R2 (gene IL1R2; UniProt P27930) is a decoy receptor that binds IL-1β with high affinity but has a truncated cytoplasmic tail incapable of signalling. It functions primarily to sequester IL-1β (and to a lesser degree IL-1α) in the extracellular space, reducing the available pool for IL-1R1 engagement. IL-1R2 is shed from the cell surface as a soluble decoy receptor (sIL-1R2), whose circulating levels increase as part of the regulatory anti-inflammatory response. needs-replication — quantitative data on how sIL-1R2 changes with age in human plasma are limited to small cross-sectional studies.
Soluble receptors
Both IL-1R1 and IL-1R2 undergo proteolytic ectodomain shedding. Soluble forms (sIL-1R1; sIL-1R2) retain ligand-binding capacity and contribute to buffering extracellular IL-1 tone, but their relative quantitative contributions in aged tissue are not established 3. needs-replication
Signal transduction
The canonical IL-1 transduction cascade proceeds from receptor engagement to NF-κB and MAPK activation through a conserved adaptor chain, confirmed by Reactome pathway R-HSA-9020702 5 3:
IL-1α or IL-1β
→ binds IL-1R1 (extracellular domains D1–D2)
→ IL-1RAcP recruited (forms ternary signalling complex)
→ cytoplasmic TIR domains of IL-1R1 + IL-1RAcP brought into proximity
→ MyD88 (adaptor; [[myd88]]) recruited via TIR–TIR interaction (C-terminus of MyD88 binds the IL-1R1/IL-1RAcP heterocomplex)
→ MyD88 mediates IRAK recruitment to the receptor complex (IRAK4 and IRAK1/2; [[irak4]])
→ IRAK4 autophosphorylation → phosphorylates IRAK1 and IRAK2
→ IRAK1/2 dissociate from receptor complex
→ TRAF6 (E3 ubiquitin ligase; [[traf6]]) recruited
→ TRAF6 catalyses K63-linked polyubiquitin chains on itself and IRAK1
→ TAK1 (MAP3K7) + TAB1/2 complex activated by K63-ubiquitin scaffold
├─ IKK arm: TAK1 → IKKβ (within IKK complex: IKKα/IKKβ/NEMO)
│ → IκBα phosphorylation (Ser32/Ser36) → proteasomal degradation
│ → NF-κB (p65/p50) nuclear translocation → pro-inflammatory gene transcription
└─ MAPK arm: TAK1 → MKK3/6 → p38 MAPK
→ MKK4/7 → JNK
→ AP-1 activation; cytokine mRNA stabilisation
Adaptor pages (R28): myd88, irak4, traf6, and tak1 are now verified atomic protein pages with full mechanistic detail. The signal transduction arrows above are anchored to those atomic pages 5.
PI3K arm
IL-1R1 Tyr496 phosphorylation recruits the p85 regulatory subunit of PI3-kinase → Akt activation, integrating IL-1 signalling with the pi3k-akt-pathway and mtor axes 6. This arm is less well-characterised in the aging context; its contribution to inflammaging is likely minor relative to the NF-κB arm.
Negative regulation
Four major regulatory mechanisms oppose IL-1 signal output:
| Mechanism | Effector | Mode | Notes |
|---|---|---|---|
| Competitive antagonism | IL-1Ra (IL1RN) | Occupies IL-1R1 without recruiting IL-1RAcP; no signal | Requires ~100–1000× molar excess over IL-1β; basis of anakinra |
| Decoy receptor sequestration | IL-1R2 | High-affinity IL-1β/α binding; no intracellular TIR; no signal | Soluble shed form (sIL-1R2) extends decoy capacity into extracellular space |
| Signalling inhibitor | SIGIRR (TIR8; IL1RL2) | Single Ig-domain protein; recruits IRAK and TRAF6 away from productive signalling | Expressed highly in gut epithelium; loss accelerates colitis |
| Ubiquitin editing | A20 (TNFAIP3) | Removes K63-ubiquitin from TRAF6; dampens downstream kinase activation | Shared with TNF/TLR/NF-κB pathways; age-associated decline in A20 expression proposed |
IL-1Ra is the dominant physiological regulator and the one best-validated therapeutically. See il-1ra for the full Il1rn biology and anakinra data.
Aging connection
IL-1β as the central SASP cytokine
IL-1β is the single most-studied cytokine in the senescence-associated secretory phenotype (SASP). Senescent cells constitutively activate the NLRP3 inflammasome through accumulated cytosolic DNA and mitochondrial ROS, generating continuous caspase-1 activity and IL-1β output 3. This IL-1β acts on IL-1R1 in neighbouring non-senescent cells, activating NF-κB and propagating the inflammatory state — a paracrine inflammaging mechanism.
IL-1β output from senescent cells is also amplified by IL-1α in an autocrine loop: IL-1α (constitutively expressed on senescent cell surfaces) signals through IL-1R1 → NF-κB → more IL-6, IL-8, MMP production, which further upregulates IL-1β transcription. This IL-1α/IL-1β autocrine-paracrine amplification loop is the proposed molecular engine of SASP maintenance (see il-1a for the primary evidence).
Hematopoietic stem cell inflammaging via IL-1
Chronic low-level IL-1 signalling drives myeloid-biased differentiation of HSCs in aged bone marrow. Kovtonyuk et al. (2022, Blood) showed that microbiota-derived signals elevate steady-state IL-1α/β in aged mouse bone marrow; IL-1R1-deficient HSCs (or antibiotic-treated mice) maintained balanced lymphoid/myeloid output 7. This implicates the IL-1 pathway in the clonal myeloid bias that precedes clonal hematopoiesis and CHIP. For the full CHIP/HSC aging context see chronic-inflammation and the implicit stubs hematopoietic-stem-cells, clonal-hematopoiesis.
| Dimension | Status |
|---|---|
| Pathway conserved in humans? | yes — IL-1R1, IL1RAP, MYD88, IRAK1/4, TRAF6 all conserved with high homology |
| Phenotype (inflammaging) conserved in humans? | yes — CANTOS demonstrated the IL-1β limb causally mediates cardiovascular events in humans 1 |
| Replicated in humans? | yes (CANTOS, n=10,061); partial (HSC myeloid bias — mechanistic data primarily murine) |
CANTOS and the aging-context druggability rationale
The CANTOS trial 1 randomised 10,061 post-MI patients with hsCRP ≥2 mg/L to canakinumab (50, 150, or 300 mg q3mo SC) vs placebo. The 150 mg arm reduced MACE (HR 0.85, 95% CI 0.74–0.98; P=0.021). No LDL reduction was observed — establishing that the CV benefit is inflammation-mediated, not lipid-mediated. This is the single most powerful human proof-of-concept for the IL-1 pathway as a geroprotective target.
Druggability-tier rationale (tier 1): Per CLAUDE.md pathway-schema, the aging-context tier reflects whether a clinical drug exists for an aging indication engaging this pathway. Three FDA-approved IL-1 modulators exist (anakinra, canakinumab, rilonacept), and CANTOS constitutes an aging-relevant Phase 3 trial (post-MI patients selected on inflammatory biomarker; outcome is cardiovascular aging, not a rare genetic syndrome). Tier 1 is justified. See canakinumab for per-arm effect sizes; il-1ra for anakinra compound data.
Therapeutic landscape
| Agent | Mechanism | Specificity | Approved indication | Aging relevance |
|---|---|---|---|---|
| Anakinra (Kineret) | Recombinant IL-1Ra; competitive IL-1R1 antagonist | IL-1R1 — blocks IL-1α and IL-1β equally | RA, CAPS, SJIA, NOMID | T2D (Larsen 2007 NEJM, n=70); HFpEF (D-HART, n=12); short half-life (4–6 h) requires daily SC injection |
| canakinumab (Ilaris) | Anti-IL-1β IgG1κ mAb | IL-1β-specific; does not block IL-1α | CAPS, SJIA, TRAPS, FMF, gout | CANTOS (n=10,061): HR 0.85 at 150 mg; cost/safety barrier to population use 1 |
| Rilonacept (Arcalyst) | IL-1 Trap (Fc–IL-1R1–IL-1RAcP fusion) | Sequesters IL-1α + IL-1β; similar breadth to anakinra | CAPS, recurrent pericarditis | No large aging-specific trial; long half-life (~7 days) better than anakinra; no CANTOS-equivalent |
| Bermekimab (investigational) | Anti-IL-1α mAb | IL-1α-specific | Phase 2/3 (hidradenitis suppurativa, atopic dermatitis) | Tests the IL-1α → SASP apex hypothesis; no aging RCT yet |
| Isunakinra (investigational) | Anti-IL-1R1 mAb | Blocks IL-1R1 directly | Phase 1–2 (asthma) | Would block all IL-1R1 ligands; not yet aging-focused |
CANTOS lessons for pathway-level therapeutics:
- IL-1β–specific blockade is sufficient to reduce MACE in a high-inflammaging population (hsCRP ≥2 mg/L), but the effect size is modest (HR 0.85) and the benefit is offset by a higher rate of fatal infection (incidence rate ratio ~1.7 vs placebo: 0.31 vs 0.18 events per 100 person-years in pooled canakinumab vs placebo; P=0.02).
- Broad IL-1 blockade (anakinra) suppresses both IL-1α and IL-1β; this may enhance efficacy in SASP-driven contexts (where IL-1α is the apex regulator) but carries a wider immunosuppression risk.
- No senolytic intersection trial has combined IL-1 pathway blockade with senescent cell clearance (e.g., fisetin or navitoclax). This is a proposed next experimental step. needs-human-replication
Cross-references
- il-1b — primary pathological ligand; NLRP3-processed; CANTOS target
- il-1a — alarmin; constitutive; SASP apex regulator; nuclear intracrine activity
- il-1ra — endogenous antagonist; basis of anakinra
- il-1r1 — primary signalling receptor; ligand selectivity; TIR domain
- il-18 — IL-1 family member with distinct receptor and IFN-γ–inducing role
- canakinumab — anti-IL-1β mAb; CANTOS trial data canonical home
- nlrp3-inflammasome — upstream source of processed IL-1β; verified pathway page
- caspase-1 — protease that activates pro-IL-1β and pro-IL-18
- nf-kb — primary downstream transcriptional effector arm
- ras-mapk — parallel MAPK arm (p38, JNK) downstream of TAK1
- sasp — major functional output of chronic IL-1 signalling in senescent cells
- chronic-inflammation — hallmark MOC; IL-1 pathway is a core molecular driver
- cellular-senescence — SASP-derived IL-1α/β sustains senescent state via IL-1R1 → NF-κB loop
Adaptor cascade (verified R28):
- myd88 — universal IL-1R/TLR adaptor; Myddosome 6:4:4 (MyD88:IRAK4:IRAK2)
- irak4 — master serine/threonine kinase; first kinase in the IL-1 signalling cascade
- traf6 — E3 ubiquitin ligase; K63-polyubiquitin scaffold
- tak1 — MAP3K7; proximal to IKK and MAPK arms
Implicit stubs created by this page:
- il-1racp — co-receptor (IL1RAP); not yet seeded
- il-1r2 — decoy receptor; not yet seeded
- sigirr — negative regulator; not yet seeded
- anakinra — recombinant IL-1Ra compound page (noted as stub in il-1ra and canakinumab)
- rilonacept — IL-1 Trap compound page; noted in il-1r1
- il-33 — IL-1 family alarmin with senescence relevance; not yet seeded
- hematopoietic-stem-cells — target of chronic IL-1 in bone marrow aging
- clonal-hematopoiesis — downstream consequence of IL-1–driven HSC bias
Limitations and gaps
- WikiPathways ID: Not retrieved (403 error during seeding). Populate
wikipathways:on next lint pass using the WikiPathways REST API or browser lookup for “IL-1 signaling human.” Tag: needs-canonical-id - KEGG precision: hsa04060 is the cytokine-cytokine receptor interaction map, not an IL-1-specific intracellular cascade entry. Reactome R-HSA-9020702 is more specific for the transduction cascade and should be the primary reference. If a dedicated KEGG IL-1 signalling pathway entry exists (check KEGG PATHWAY + hsa + search “interleukin-1”), update the
kegg:field. needs-canonical-id - Reactome ID conflict in nf-kb: The nf-kb.md page incorrectly lists
reactome: R-HSA-9020702; this ID belongs to IL-1 signaling. Correct the nf-kb.md Reactome field on next lint pass (but do not modify other pages in this seeding pass). - MyD88/IRAK4/TRAF6/TAK1 (resolved R28-2026-05-07): All four adaptor protein pages are now seeded and verified. Signal transduction wikilink graph is complete.
- IL-1α / SASP apex claim: The claim that IL-1α is the “apex regulator” of the SASP relies on Orjalo et al. 2009 (verified on il-1a). That verification is recorded on the atomic page; the pathway page inherits the claim by wikilink without repeating the evidence. No additional gap.
- IL-1R2 aging data: Quantitative data on age-associated changes in sIL-1R2 levels are sparse; the decoy receptor’s contribution to IL-1 buffering in aged tissue is incompletely characterised. needs-replication
- Senolytic intersection: No published trial combining IL-1 pathway blockade with senolytic clearance (navitoclax, fisetin). This remains an important next experiment. needs-human-replication
- Hematopoietic aging claim: Kovtonyuk 2022 (Blood) is a mouse study; the microbiome–IL-1–HSC axis in human aging is inferred but not directly tested. needs-human-replication
- IL-33 in senescence: Emerging evidence that IL-33 is released from senescent cell nuclei on lytic death (alarmin function); no atomic page yet. needs-replication; il-33 is an implicit stub.
Footnotes
Footnotes
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doi:10.1056/NEJMoa1707914 · Ridker PM et al. · NEJM 2017 · rct · n=10,061 (placebo n=3344; 50 mg n=2170; 150 mg n=2284; 300 mg n=2263) · post-MI patients with hsCRP ≥2 mg/L; canakinumab 50/150/300 mg q3mo SC vs placebo; median follow-up 3.7 yr; primary endpoint MACE; 150 mg arm HR 0.85 (95% CI 0.74–0.98; P=0.021); hsCRP −37 pp vs placebo at 48 months (150 mg arm); no LDL change; fatal infection incidence rate ratio ~1.7 (0.31 vs 0.18 events/100 person-years; P=0.02); local PDF: — canonical CANTOS numerics on canakinumab ↩ ↩2 ↩3 ↩4
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doi:10.1111/imr.12621 · Dinarello CA · Immunol Rev 2018 · review · IL-1 family overview including all 11 members, receptor architecture, TIR-domain signalling, and negative regulation; ~1731 citations; OA (green PMC5756628); DOI lookup failed — not locally available ↩
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doi:10.1182/blood-2010-07-273417 · Dinarello CA · Blood 2011 · review · comprehensive coverage of IL-1β central role in acute and chronic inflammation; TIR-domain signalling; therapeutic neutralisation; ~2149 citations; OA (bronze); not yet locally downloaded ↩ ↩2 ↩3 ↩4
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doi:10.1074/jbc.270.23.13757 · Greenfeder SA et al. · J Biol Chem 1995 · in-vitro (molecular cloning, binding studies) · cloned IL-1RAcP as the obligate co-receptor for IL-1R1 signalling; showed IL-1Ra occupies IL-1R1 without recruiting IL-1RAcP; structural basis of antagonism; ~638 citations; local PDF available ↩
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doi:10.1016/s1074-7613(00)80402-1 · Wesche H et al. · Immunity 1997 · in-vitro (co-immunoprecipitation, kinase assay) · identified MyD88 as the TIR-domain adaptor recruited to IL-1R1 upon ligand binding; showed MyD88 recruits IRAK to the receptor complex; ~1104 citations; local PDF available ↩ ↩2
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Cross-reference to il-1r1 atomic page (verified 2026-05-06) for IL-1R1 Tyr496 phosphorylation → PI3K-p85 interaction claim; canonical source is Boraschi & Tagliabue 2013 (doi:10.1016/j.smim.2013.10.023) as cited there ↩
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doi:10.1182/blood.2021011570 · Kovtonyuk LV et al. · Blood 2022 · in-vivo (mouse) · microbiota-derived signals elevate steady-state IL-1α/β in aged bone marrow; IL-1R1 KO HSCs maintain balanced lymphomyeloid output; antibiotic suppression phenocopies; ~135 citations; OA (hybrid); not yet locally downloaded; needs-human-replication ↩