il-1b

IL-1β (IL1B)

The master pro-inflammatory cytokine of inflammaging. IL-1β is the defining output of the NLRP3 inflammasome: a caspase-1 substrate that requires both a transcriptional priming step and a danger-sensing activation step before secretion. It is the only cytokine whose therapeutic neutralisation has been proven in a cardiovascular RCT (canakinumab, CANTOS 2017), establishing a causal link between chronic sterile inflammation and atherosclerotic events. Twelve wiki pages currently link here.

Identity

• UniProt: P01584 (IL1B_HUMAN) — Swiss-Prot (manually curated); accessed 2026-05-05
• NCBI Gene: 3553 (symbol: IL1B; synonym IL1F2)
• HGNC: 5992
• Mouse ortholog: Il1b (one-to-one)
• Gene locus: 2q14.1
• Precursor length: 269 amino acids (pro-IL-1β; ~31 kDa)
• Mature form: residues 117–269, 153 amino acids (~17 kDa)

Naming note

The file name il-1b.md is canonical for the cytokine. No pathways/il-1b.md exists; the relevant pathway page is nlrp3-inflammasome. Aliases above cover the common variant spellings used across inbound links.

Processing and structure

Pro-IL-1β is synthesised as a leaderless 31 kDa precursor with no signal peptide, and is therefore not secreted via the classical ER-Golgi pathway ¹². Processing has two steps:

1. Caspase-1 cleavage at Asp116/Ala117 — removes the 116-residue propeptide and releases the 17 kDa mature cytokine ³⁴. ICE (IL-1β Converting Enzyme), subsequently renamed caspase-1, was identified in 1989 as the responsible protease ⁵.
2. Secretion via GSDMD pores — caspase-1 simultaneously cleaves gsdmd (gasdermin D) at Asp275; the liberated N-terminal GSDMD fragment oligomerises in the plasma membrane to form ~18 nm pores ⁶. Mature IL-1β exits through these pores. At high pore density, cells undergo pyroptosis — a lytic, immunogenic death.

Alternative cleavage at positions 105–106 and 115–116 by the extracellular Streptococcus pyogenes protease SpeB produces active IL-1β in an inflammasome-independent manner (UniProt P01584, annotation note).

Distinct from IL-1α

IL-1α and IL-1β are both IL-1 family members that bind IL-1R1 with similar affinity, but their biology is fundamentally different:

Property	IL-1α	IL-1β
Signal peptide	absent	absent
Constitutive expression	yes	low baseline
Active form	full-length precursor	caspase-1–cleaved mature form
Release mechanism	necrotic cell lysis (alarmin)	GSDMD pores; pyroptosis
Requires inflammasome	no	yes (canonical)

Anakinra (recombinant IL-1Ra) blocks both via IL-1R1 antagonism. canakinumab (anti-IL-1β mAb) is IL-1β-specific.

Two-signal model of IL-1β production

The canonical inflammasome model requires two independent signals before IL-1β is secreted ⁴:

Signal 1 — Priming (transcriptional)

TLR ligands (LPS), cytokines (IL-1β itself, TNF), or oncogenic signals activate NF-κB via the NF-κB pathway → transcription of IL1B mRNA and NLRP3 mRNA. This step generates the substrate (pro-IL-1β) and the sensor (nlrp3). Without priming, cells have negligible amounts of either.

Signal 2 — Activation (post-translational)

Danger-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) trigger NLRP3 oligomerisation:

• Extracellular ATP — binds P2X7 receptor → K⁺ efflux
• Potassium efflux — a convergent upstream signal that activates NLRP3 directly
• Monosodium urate (MSU) and cholesterol crystals — phagocytosis → lysosomal damage → K⁺ efflux
• β-amyloid — activates NLRP3 in microglia ⁷
• Palmitate and glucose — activate pancreatic β-cell NLRP3

Activated NLRP3 recruits the adaptor asc to form the ASC speck → procaspase-1 recruitment → autoproteolysis → active caspase-1 → cleavage of pro-IL-1β and GSDMD.

Receptor system

Receptor	Gene	Function
IL-1R1	IL1R1	Signalling receptor; pairs with IL-1RAcP (IL1RAP) co-receptor
IL-1R2	IL1R2	Decoy receptor; binds IL-1β without signalling; sequesters cytokine
IL-1Ra	IL1RN	Endogenous antagonist; competes with IL-1 for IL-1R1 binding

Downstream of IL-1R1: MyD88 → IRAK1/IRAK4 → TRAF6 → TAK1 → IKK complex → NF-κB nuclear translocation + JNK and p38 MAPK → transcription of IL-6, TNF, COX-2, iNOS, matrix metalloproteinases.

This creates a positive feedback loop: IL-1β → IL-1R1 → NF-κB → more IL-1β (via Signal 1 priming) + IL-6 production.

Inflammaging axis

Franceschi et al. (2000) coined the term inflamm-aging to describe the chronic low-grade sterile inflammation that rises with age and drives multiple age-associated diseases ⁸. IL-1β is one of its canonical effectors:

• Serum IL-1β rises modestly with age in humans, though the signal is smaller and more variable than IL-6 or TNF (#gap/contradictory-evidence — some cross-sectional studies find no age-dependent rise in circulating IL-1β; tissue and monocyte-intracellular data are cleaner).
• NLRP3 in aged macrophages — NLRP3 priming is chronically elevated in aged macrophages due to constitutive NF-κB activation; even weak Signal 2 stimuli elicit exaggerated IL-1β secretion needs-replication.
• IL-1β → NF-κB → IL-6 → CRP → MACE axis — CANTOS proved this axis is causally relevant to cardiovascular outcomes: canakinumab reduced MACE independently of LDL lowering. For quantitative effect sizes, see canakinumab and atherosclerosis.

Dimension	Status
Pathway conserved in humans?	yes — IL1B, IL1R1, caspase-1 all conserved
Phenotype (inflammaging) conserved in humans?	yes — CANTOS, CHIP-CVD evidence
Replicated in humans?	yes (cardiovascular endpoint); partial (cellular aging mechanisms)

Disease landscape

Cardiovascular disease and CANTOS

The CANTOS trial (Ridker 2017, NEJM; n=10,061; phase 3 RCT) demonstrated that canakinumab (anti-IL-1β mAb) reduced recurrent MACE in post-MI patients with elevated hsCRP, independent of LDL levels ⁹. For quantitative effect sizes (HR, p-values, infection rates), see canakinumab — that page is the canonical home for CANTOS data.

Clonal hematopoiesis / TET2-CHIP

TET2 loss-of-function clonal hematopoiesis (CHIP) confers elevated CVD risk. Fuster et al. (2017, Science) showed that TET2-deficient macrophages hyperproduce IL-1β in an NLRP3-dependent manner, and that NLRP3 inhibition or IL-1β blockade abolishes the accelerated atherosclerosis in Ldlr-/- mice transplanted with Tet2-/- bone marrow ¹⁰. This places IL-1β as the mechanistic effector connecting CHIP to cardiovascular aging. See clonal-hematopoiesis and tet2.

Dimension	Status
Pathway conserved in humans?	yes
Phenotype conserved in humans?	in-progress — human CHIP-CVD association well-established; IL-1β mechanism inferred
Replicated in humans?	no — mechanistic human CHIP + IL-1β blockade trial needed

needs-human-replication (TET2-CHIP mechanism)

Alzheimer’s disease

β-amyloid (Aβ) activates NLRP3 in microglia → IL-1β secretion → neuroinflammation. Heneka et al. (2013, Nature) showed in 16-month-old APP/PS1 mice that NLRP3 or caspase-1 deficiency (a) reduces brain IL-1β and caspase-1 activation, (b) reduces hippocampal/cortical Aβ burden by ~70% (FA-extractable Aβ), (c) rescues spatial memory in the Morris Water Maze, and (d) skews microglia from an M1-like (NOS2+) toward an M2-like (arginase-1+, FIZZ1+) phenotype with enhanced Aβ phagocytosis ⁷. The inflammatory skewing involves the full NLRP3/caspase-1 axis, with IL-1β as one output; the paper does not isolate IL-1β alone as the M1 driver. See alzheimers-disease.

Dimension	Status
Pathway conserved in humans?	yes
Phenotype conserved in humans?	partial — NLRP3 and IL-1β elevated in human AD brain; no successful IL-1β-targeting trial in AD yet
Replicated in humans?	no needs-human-replication

CAPS (cryopyrin-associated periodic syndromes)

Gain-of-function missense mutations in exon 3 of CIAS1 (the gene encoding cryopyrin, later renamed NLRP3) cause constitutive NLRP3 activation → uncontrolled IL-1β → autoinflammatory disease (FCAS, MWS, NOMID spectrum) ¹¹. Hoffman et al. identified four distinct mutations across 3 FCAS families and 1 MWS family: A439V, V198M, E627G (FCAS), and A352V (MWS), all in exon 3, absent in >100 normal controls. Canakinumab is FDA-approved for CAPS, establishing clear human proof of concept for the NLRP3 → IL-1β → systemic inflammation axis.

Type 2 diabetes

Palmitate and high-glucose activate β-cell NLRP3 → IL-1β → paracrine β-cell dysfunction and apoptosis. Anakinra (IL-1Ra) showed modest improvement in β-cell function in a small RCT needs-replication. See type-2-diabetes.

Crystal arthropathies

Monosodium urate (gout) and calcium pyrophosphate (pseudogout) crystals are canonical Signal 2 stimuli for NLRP3 → IL-1β. IL-1 blockade (anakinra, canakinumab) is effective in refractory gout.

Mouse genetics

Il1b-deficient mice are viable, fertile, and grossly normal under specific-pathogen-free conditions, but display resistance to fever induction (LPS, turpentine) and impaired acute-phase response ¹²¹³. Horai et al. (1998) additionally showed that IL-1β (but not IL-1α) is crucial for turpentine-induced fever and glucocorticoid secretion using mice deficient in IL-1α, IL-1β, IL-1α/β, and IL-1Ra, produced by gene targeting. Reduced collagen-induced arthritis severity and protection from MSU-crystal-induced inflammation have been reported in subsequent work.

Nlrp3 gain-of-function knock-in mice (constitutively active Nlrp3 D301N or A350V) die perinatally or in early adulthood with severe multi-organ inflammation, demonstrating that tonic NLRP3-IL-1β signalling is lethal unsourced (citation needed for specific KI line).

Dimension	Status
Pathway conserved in humans?	yes — Il1b KO and human IL-1β biology directly parallel
Phenotype conserved in humans?	yes — CAPS (NLRP3 GoF) is the human equivalent of murine NLRP3 GoF
Replicated in humans?	yes (CAPS); partial (atherosclerosis, CANTOS)

Therapeutic landscape

Agent	Mechanism	Target	Status
anakinra	Recombinant IL-1Ra	IL-1R1 (blocks both IL-1α and IL-1β)	FDA-approved (RA, CAPS, SJIA, NOMID)
canakinumab	Anti-IL-1β mAb (IgG1κ)	IL-1β (specific)	FDA-approved (CAPS, SJIA, gout); CANTOS phase 3
Rilonacept	IL-1 Trap (Fc-IL-1R1-IL-1RAcP)	IL-1α + IL-1β	FDA-approved (CAPS); orphan use
MCC950	NLRP3 NACHT domain inhibitor	NLRP3 activation	Preclinical; multiple phase II underway
OLT1177 (dapansutrile)	NLRP3 inhibitor	NLRP3 activation	Phase II (acute gout, HFpEF)

For compound-level PK, dosing, and trial data: see canakinumab, anakinra, senomorphics.

Aging-context tier-1 rationale. Canakinumab is FDA-approved for cryopyrin-associated periodic syndromes (CAPS), systemic juvenile idiopathic arthritis (SJIA), and gouty arthritis — all rare autoinflammatory indications, not aging-rejuvenation. Anakinra (IL-1Ra) and rilonacept (IL-1 Trap) carry similar autoinflammatory-disease approvals. The aging-context tier-1 designation reflects (a) the CANTOS Phase 3 RCT (n=10,061) demonstrating that IL-1β neutralization causally reduces cardiovascular events independent of LDL — the most direct human-RCT validation that any inflammaging cytokine is causal for an age-related disease — and (b) IL-1β’s mechanistic centrality as the master NLRP3-inflammasome output. Strict Open Targets Approved Drug = true for an aging indication does not apply, but CANTOS arguably represents the strongest human-evidence anchor of any tier-1 protein on this wiki.

Pathway membership and cross-references

• il-1-signaling — integrating pathway page for the IL-1 family (verified R27); receptor architecture, MyD88-IRAK-NF-κB cascade, and antagonist biology
• nlrp3-inflammasome — upstream processor; IL-1β is the primary output
• nf-kb — both upstream (Signal 1 priming) and downstream (post-receptor signalling)
• jak-stat-pathway — secondary signalling downstream of IL-1R1 in some contexts
• chronic-inflammation — hallmark context; IL-1β is a canonical driver
• atherosclerosis — disease context; CANTOS
• clonal-hematopoiesis — TET2-CHIP → IL-1β CVD axis
• microglia — key cellular source in CNS
• alzheimers-disease — neuroinflammation context
• type-2-diabetes — β-cell NLRP3-IL-1β axis
• canakinumab — therapeutic antibody; verified R12

Family-completion cross-links (R24 + R25 + R27 seeded): caspase-1 (R24d), asc (R24d), gsdmd (R24d), pyroptosis (R24d), il-1r1 (R25), il-1a (R25), il-1ra (R25), il-18 (R25), tet2 (verified), il-1-signaling (pathway, R27), anakinra (compound, R27). The IL-1 family page-cluster is now schematically complete.

Limitations and gaps

• Serum IL-1β as a biomarker: Circulating IL-1β is often below the detection limit of standard ELISAs in healthy humans; its rise with age is inconsistent across cohorts. Intracellular/tissue measures are more reliable but not widely used clinically. contradictory-evidence
• Il1b-/- KO paper: Resolved — canonical references are Zheng et al. 1995 (Immunity, single Il1b-/- KO) and Horai et al. 1998 (J Exp Med, multi-KO comparison). Both DOIs now in footnotes.
• NLRP3 GoF KI mouse citation: Formal citation for the perinatally lethal Nlrp3 D301N or A350V constitutive-active knock-in lines not confirmed. unsourced (citation needed for specific KI line — likely Brydges 2009 J Clin Invest or Meng 2009 EMBO; verify on next pass).
• Inflammaging mechanistic loop: The claim that aged macrophages have chronically elevated NLRP3 priming needs a specific primary citation needs-replication.
• Type 2 diabetes anakinra RCT data needs size and effect-size citation added on the type-2-diabetes page. dose-response-unclear
• Howard 1991 DOI: PMID 1919001 confirmed; no DOI in the PubMed record (predates DOI registration). Footnote uses PMID.
• Black 1989 DOI: PMID 2784432 confirmed; no DOI in the PubMed record (J Biol Chem 1989). Footnote uses PMID.
• Closed-access sources not re-verified against full text: Auron 1984 (PNAS), March 1985 (Nature), Cerretti 1992 (Science), Black 1989 (J Biol Chem), Howard 1991 (J Immunol), Franceschi 2000 (Ann NY Acad Sci), Shi 2015 (Nature), Fuster 2017 (Science) — all either not_oa or pending in a local paper archive. Claims sourced to these are consistent with well-established consensus biology but have not been verified line-by-line against the PDFs. no-fulltext-access (partial)

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Footnotes

Footnotes

1. doi:10.1073/pnas.81.24.7907 · Auron PE et al. · PNAS 1984 · in-vitro (cDNA sequencing, human monocyte mRNA) · first cDNA sequence of human IL-1β precursor; defined 269-aa structure ↩

2. doi:10.1038/315641a0 · March CJ et al. · Nature 1985 · in-vitro · cloning and expression of two distinct IL-1 cDNAs (α and β); established distinct gene products ↩

3. PMID:1919001 · Howard AD et al. · J Immunol 1991 · in-vitro · mapped caspase-1 cleavage requirement to aspartate residues; showed ICE cleaves pro-IL-1β but not IL-1α ↩

4. doi:10.1126/science.1373520 · Cerretti DP et al. · Science 1992 · in-vitro (molecular cloning) · molecular cloning of ICE (caspase-1); established it as the dedicated pro-IL-1β processing enzyme ↩ ↩²

5. PMID:2784432 · Black RA et al. · J Biol Chem 1989 · in-vitro (human leukocyte extract) · identification of a pre-aspartate-specific protease that cleaves pro-IL-1β; later renamed caspase-1/ICE ↩

6. doi:10.1038/nature15514 · Shi J et al. · Nature 2015 · in-vitro + in-vivo (mouse) · discovery that caspase-1 cleaves GSDMD; GSDMD N-terminal fragment forms membrane pores; IL-1β exits via pores; high-density pores → pyroptosis ↩

7. doi:10.1038/nature11729 · Heneka MT et al. · Nature 2013 · in-vivo (APP/PS1 mouse × Nlrp3-/- or Casp-1-/-) · n not stated per group in main text; mice analyzed at 16 months · NLRP3/caspase-1 deficiency reduces brain Aβ burden (~70% FA-extractable Aβ reduction), rescues spatial memory (MWM), skews microglia to M2 phenotype with enhanced phagocytosis; human AD/MCI brains show elevated cleaved caspase-1 · model: C57Bl/6 APP/PS1 × Nlrp3-/- · local PDF: ↩ ↩²

8. doi:10.1111/j.1749-6632.2000.tb06651.x · Franceschi C et al. · Ann NY Acad Sci 2000 · review · coined “inflamm-aging”; defined chronic low-grade sterile inflammation as a driver of aging and age-related disease ↩

9. doi:10.1056/NEJMoa1707914 · Ridker PM et al. · NEJM 2017 · rct · n=10,061 · phase 3; post-MI patients with hsCRP ≥2 mg/L; canakinumab 150 mg q3m vs placebo · local PDF: · for effect sizes, see canakinumab ↩

10. doi:10.1126/science.aag1381 · Fuster JJ et al. · Science 2017 · in-vivo (mouse, bone-marrow transplant) · TET2-deficient macrophages hyperproduce IL-1β via NLRP3; NLRP3 inhibition abolishes accelerated atherosclerosis in Ldlr-/- recipients · model: Tet2-/- BMT → Ldlr-/- mice ↩

11. doi:10.1038/ng756 · Hoffman HM et al. · Nature Genetics 2001 · observational (human genetics) · n=3 FCAS families + 1 MWS family (4 families total); >100 normal controls sequenced · identified 4 missense mutations in exon 3 of CIAS1 (cryopyrin/NLRP3): A439V, V198M, E627G (FCAS) and A352V (MWS); all absent in controls; established CIAS1 (NLRP3) as cause of FCAS and MWS · local PDF: ↩

12. doi:10.1016/1074-7613(95)90154-x · Zheng H et al. · Immunity 1995 · in-vivo (gene-targeted mouse) · canonical Il1b-/- single-KO characterization; mice viable and fertile; resistant to LPS/influenza-induced fever; impaired acute-phase response (reduced SAP, fibrinogen); model: Il1b-/- C57BL/6 × 129 ↩

13. doi:10.1084/jem.187.9.1463 · Horai R et al. · J Exp Med 1998 · in-vivo (gene-targeted mouse) · produced IL-1α-/-, IL-1β-/-, IL-1α/β-/-, and IL-1Ra-/- mice; showed IL-1β (not IL-1α) is crucial for turpentine-induced fever and glucocorticoid secretion; IL-1β-/- mice show impaired collagen-induced arthritis · model: multiple Il1 KO lines ↩