il-1a

IL-1α (IL1A)

The alarmin-cytokine duality of inflammaging. IL-1α is the constitutively expressed, dual-compartment member of the IL-1 family: its precursor form is biologically active as a nuclear chromatin-binding transcription regulator, and its released form signals through IL-1R1 identically to IL-1β. Critically for aging, senescent cells maintain surface-bound and secreted IL-1α as the upstream master regulator of the full SASP cytokine network — IL-1α blockade abrogates downstream IL-6 and IL-8 induction. This places IL-1α at the apex of senescent-cell paracrine signalling, distinct from and parallel to the NLRP3-driven IL-1β axis.

Identity

• UniProt: P01583 (IL1A_HUMAN) — Swiss-Prot (manually curated)
• NCBI Gene: 3552 (symbol: IL1A; synonym IL1F1)
• HGNC: 5991
• Ensembl: ENSG00000115008
• Mouse ortholog: Il1a (one-to-one)
• Gene locus: 2q14.1 (co-localised with IL1B on chromosome 2)
• Precursor length: 271 amino acids (pro-IL-1α; ~31 kDa)
• Mature form: residues 113–271, cleaved by calpain-1 (CAPN1) at Asp112; ~18 kDa

Naming note

File il-1a.md is canonical for the cytokine. No pathways/il-1a.md exists; the relevant pathway page is il-1-signaling. Aliases cover common spellings found across inbound links; il-1b is the sibling page for IL-1β. Note: il-1a here is the protein; no naming conflict with a pathway page exists because the pathway is titled [[il-1-signaling]] per the IL-1 receptor pathway convention.

Processing, structure, and the dual-activity model

Structural class

IL-1α adopts the beta-trefoil fold common to the IL-1 family — twelve beta-strands arranged in a trefoil pattern — enabling IL-1R1 binding with affinity similar to IL-1β ¹. Unlike IL-1β, both the precursor form (pro-IL-1α, 31 kDa) and the mature form (~18 kDa) are biologically active — no caspase-1-dependent cleavage step is required for receptor signalling.

Nuclear compartment — intracrine activity

Pro-IL-1α contains a nuclear localisation signal (NLS) at residues 82–86 (UniProt P01583; the KVLKKRR motif in the N-terminal propiece) that directs the uncleaved precursor to the nucleus upon inflammatory stimuli (LPS, IL-1, TNF) ². Once nuclear:

• Pro-IL-1α activates transcription in an IL-1R-independent (intracrine) manner, driving NF-κB- and AP-1-regulated genes; in a GAL4-reporter system the pIL-1α chimera activated transcription 90-fold, while the mature form (mIL-1α) was without activity ².
• The nuclear precursor physically interacts with histone acetyltransferase complexes — specifically p300, PCAF, Gcn5, and the adaptor Ada3 (components of the SAGA/PCAF transcriptional activation complex) — integrating non-destructively into the p300-PCAF complex to enhance transcriptional output ³. The paper does not demonstrate direct chromatin remodelling at specific inflammatory-gene loci; the evidence is for functional cooperation with the p300-PCAF complex via reporter and co-IP assays.
• Post-translational modifications regulate nuclear residency: Lys82 acetylation and myristoylation modulate NLS function, while Ser87 phosphorylation is linked to nuclear retention (UniProt P01583, accessed 2026-05-06).

This intracrine activity means cells constitutively expressing pro-IL-1α have an autonomous pro-inflammatory transcriptional state that does not require paracrine cytokine secretion — a key mechanistic difference from IL-1β.

Cytoplasmic and membrane compartments — alarmin activity

Unlike IL-1β, which is entirely cytoplasmic until secreted, IL-1α can be anchored to the plasma membrane inner leaflet (via N-myristoylation at Lys82/Lys83) or the outer leaflet surface (membrane-bound form), where it can engage IL-1R1 on neighbouring cells in a juxtacrine manner ⁴.

Release mechanism — alarmin: When cells die by necrosis (unregulated membrane rupture), IL-1α is rapidly released into the extracellular milieu as a danger-associated molecular pattern (DAMP/alarmin), initiating sterile inflammation without prior caspase-1 activation ⁵. This is the primary route of IL-1α release in tissue injury; it requires no inflammasome priming step.

Release from senescent cells: Senescent cells maintain both surface-bound and secreted IL-1α as a constitutive feature of the SASP (see § Role in aging below).

Canonical secretion

A minor secretion route via TMED10 (p24δ1) has been identified (UniProt P01583), and S100A13 has been implicated in the unconventional secretion pathway under stress conditions. Classical ER-Golgi secretion does not occur (no signal peptide), consistent with all IL-1 family members.

Comparison with IL-1β

Property	IL-1α	IL-1β
Signal peptide	absent	absent
Constitutive expression	yes (nuclear + cytoplasmic)	low baseline; inducible
Precursor active?	yes (full-length pro-IL-1α)	no (requires caspase-1 cleavage)
Mature form generated by	CAPN1 (calpain-1) at Asp112	caspase-1/ICE at Asp116
Release as alarmin	yes (necrosis → immediate release)	no (requires NLRP3 activation)
Requires inflammasome	no	yes (canonical)
Nuclear function	yes (intracrine transcription factor)	no
Surface-bound form	yes	no
SASP role	upstream master regulator	downstream effector

Receptor system

Both IL-1α and IL-1β bind IL-1R1 (paired with the IL-1RAcP co-receptor) to activate the canonical downstream axis: MyD88 → IRAK1/IRAK4 → TRAF6 → TAK1 → IKK → NF-κB nuclear translocation + JNK and p38 MAPK → transcription of pro-inflammatory genes (IL-6, IL-8, TNF, COX-2, matrix metalloproteinases) ¹.

IL-1α also binds the decoy receptor IL-1R2 (IL1R2), which sequesters the cytokine without intracellular signalling — a regulatory buffer for IL-1α activity (UniProt P01583).

IL-1Ra (encoded by IL1RN; see anakinra) competitively antagonises both IL-1α and IL-1β at IL-1R1.

Role in aging

IL-1α as the upstream regulator of the SASP

Orjalo et al. (2009) established the most aging-critical finding for this protein: in bleomycin-induced, replicatively senescent, oncogenic RAS^V12-induced, and NaB-induced senescent HCA2 human foreskin fibroblasts, IL-1α acts as the upstream master regulator of the senescence-associated IL-6/IL-8 cytokine network ⁴. Specifically:

• Senescent cells display IL-1α on their surface: 79% of senescent vs 20% of presenescent HCA2 cells scored surface-IL-1α-positive by FACS.
• Blocking IL-1α signalling with a neutralising antibody (0.6 μg/ml) or rIL-1Ra (240 ng/ml) markedly abrogates IL-6 and IL-8 production from senescent cells; IL-1β antibody (0.8 μg/ml) had no effect, establishing IL-1α — not IL-1β — as the upstream driver.
• IL-1α depletion reduced NF-κB (p65) and C/EBPβ DNA-binding activity in senescent cells; both transcription factors are required targets of the IL-1R1→IRAK1→NF-κB/C/EBPβ axis for IL-6/IL-8 expression.
• IRAK1 depletion (>90% by shRNA) prevented the elevated IL-6 secretion 7 days post-bleomycin, confirming IL-1R1-IRAK1 signalling is the transducing mechanism.
• The surface IL-1α → IL-1R1 autocrine/juxtacrine loop → NF-κB + C/EBPβ → IL-6/IL-8 axis constitutes a positive-feedback loop that sustains the SASP chronically after initial senescence induction.

This places IL-1α at the apex of SASP signalling in a way that IL-1β (caspase-1-cleavage-dependent, NLRP3-driven) is not. IL-1α requires no inflammasome for its SASP-driving activity.

Dimension	Status
Pathway conserved in humans?	yes — IL-1α/IL-1R1/NF-κB axis fully conserved; SASP documented in human cell culture
Phenotype (SASP induction) conserved in humans?	yes — Orjalo 2009 used human fibroblasts; confirmed in human senescence models
Replicated in aging humans in vivo?	partial — circulating IL-1α rises with age and senescent burden; no interventional RCT blocking IL-1α in human aging specifically needs-human-replication

Inflammaging and age-related disease

IL-1α contributes to inflammaging through multiple routes:

1. Senescent-cell tonic release — accumulating senescent cells constitute an expanding source of surface/secreted IL-1α with age, continuously driving downstream SASP components (IL-6, IL-8, MMP-3) that impair tissue homeostasis.
2. Necrosis/cell turnover — age-associated increases in cell death rates (tissue atrophy, DNA damage, mitochondrial dysfunction) increase necrotic IL-1α release from dying cells as a DAMPs signal.
3. Chronic tissue remodelling — IL-1α drives matrix metalloproteinase expression and stromal activation, contributing to the fibrotic and pro-tumorigenic microenvironment associated with aged tissues.

needs-human-replication — The specific contribution of IL-1α (vs IL-1β, IL-6, TNF) to aging-driven chronic sterile inflammation in humans has not been dissected in prospective interventional studies.

Mouse genetics

Horai et al. (1998) generated IL-1α-/-, IL-1β-/-, IL-1α/β double-KO, and IL-1ra-/- mice and demonstrated that IL-1α is not required for turpentine-induced fever (body temperature rose in IL-1α-/- mice similarly to wild-type controls), whereas IL-1β-/- mice failed to develop fever after turpentine injection ⁶. The same paper showed that glucocorticoid (corticosterone) induction 8 h after turpentine was suppressed in IL-1β-/- but not IL-1α-/- mice. This distinguishes the two IL-1 family members: IL-1α is dispensable for systemic febrile and HPA-axis responses while IL-1β is required. The paper also found mutual induction between IL-1α and IL-1β: IL-1α mRNA was suppressed >30-fold in IL-1β-/- brain, and IL-1β mRNA was reduced ~50% in IL-1α-/- macrophages. Note: this paper does not report contact hypersensitivity results; that phenotype was attributed to IL-1α in other studies not contained in this paper. needs-replication (contact hypersensitivity claim needs separate citation)

Dimension	Status
Pathway conserved in humans?	yes — IL-1α biology broadly conserved across mammals
Phenotype conserved in humans?	partial — Horai 1998 mouse KO shows IL-1α dispensable for fever and glucocorticoid responses in controlled turpentine model; human IL-1α biology inferred from in vitro and SASP data
Replicated in humans?	no — no IL-1α-specific genetic human data comparable to IL-1β/CANTOS; contact hypersensitivity phenotype attributed to IL-1α in other studies requires separate citation needs-human-replication

Therapeutic landscape

Bermekimab (anti-IL-1α mAb)

Bermekimab is a fully human IgG1 anti-IL-1α monoclonal antibody (XBiotech / Janssen) that specifically targets IL-1α without blocking IL-1β. It therefore represents the first therapeutic tool to dissect the IL-1α–specific contribution to disease from the broader IL-1 axis ¹. Clinical development as of 2026 has focused on:

• Atopic dermatitis — Phase 2b/3 trials (bermekimab in moderate-to-severe AD)
• Hidradenitis suppurativa — Phase 2 data
• Solid tumours — investigational (IL-1α as tumour microenvironment driver)

No aging-specific clinical trial (senescent cell burden, inflammaging) has been completed for bermekimab as of 2026. This is the primary translational gap for IL-1α in aging biology. needs-human-replication

Agents that block IL-1α and IL-1β non-selectively

Agent	Mechanism	Status
anakinra	Recombinant IL-1Ra; blocks IL-1R1	FDA-approved (RA, CAPS, SJIA)
Rilonacept	IL-1 Trap (Fc–IL-1R1–IL-1RAcP)	FDA-approved (CAPS); blocks IL-1α + IL-1β
canakinumab	Anti-IL-1β mAb	FDA-approved; IL-1β-specific; does not block IL-1α

Anakinra and rilonacept suppress the full IL-1R1 axis (both ligands); thus their beneficial effects in aging-related conditions (e.g. T2D, HFpEF trials with anakinra) may be partially mediated by IL-1α blockade, not exclusively IL-1β.

Pathway membership and cross-references

• il-1-signaling — canonical pathway page for the IL-1α/β → IL-1R1 axis
• sasp — senescence-associated secretory phenotype; IL-1α is the apex regulator
• nf-kb — both upstream (intracrine nuclear activity) and downstream (post-receptor signalling)
• cellular-senescence — hallmark context; IL-1α is a constitutive senescent-cell SASP driver
• chronic-inflammation — hallmark context; IL-1α contributes to tonic inflammaging
• nlrp3-inflammasome — parallel arm: NLRP3-driven IL-1β does not require IL-1α; but IL-1α can prime NLRP3 transcription via NF-κB
• caspase-1 — cleaves IL-1β but not IL-1α; this mechanistic distinction is definitional
• il-1b — sibling cytokine; see the comparison table in § Processing above and the full treatment in the IL-1β page
• il-1r1 — shared signalling receptor (with IL-1β and IL-1Ra)
• il-1ra — endogenous receptor antagonist; anakinra is its recombinant form
• nf-kb — key downstream transcription factor; also upstream via intracrine nuclear activity
• dna-damage-response — upstream activator: genotoxic stress induces IL-1α expression and nuclear accumulation

Limitations and gaps

• Circulating IL-1α as biomarker: Serum IL-1α is often undetectable in healthy humans (short half-life, cell-associated). Age-associated changes are documented in tissue senescence models but not robustly in population-level plasma studies. contradictory-evidence
• GTEx aging correlation: Not populated; see sops/finding-tissue-expression.md for protocol. needs-gtex-data
• Mendelian randomisation: No MR study specifically for IL1A variants and aging or longevity outcomes has been identified. mr-causal-evidence: not-tested. needs-replication
• GenAge entry: Search for IL1A in GenAge returned no entry. IL-1α is not in the current HAGR curated aging gene set despite its SASP role; genage-id: null. needs-canonical-id
• Bermekimab clinical stage for aging: No completed RCT targeting IL-1α specifically in aging contexts (senescent burden, functional decline). This is the decisive translational gap. needs-human-replication
• Werman 2004 DOI correction: The brief provided DOI 10.1073/pnas.0308686100 — this DOI returned “not found” in the archive. The correct DOI for the Werman 2004 PNAS paper (“The precursor form of IL-1α is an intracrine proinflammatory activator of transcription”) is 10.1073/pnas.0308705101. The brief DOI appears to have a typographic error in the last two digits. Verified against DOI lookup.
• Rider 2011 and Dinarello 2017 — unverifiable: Both papers failed DOI lookup (publisher paywall for Rider; no OA URL found for Dinarello). Claims attributed to these papers (alarmin release from necrotic cells for Rider; receptor biology and therapeutic overview for Dinarello) are unverified against full text. Tagged no-fulltext-access. The alarmin/necrosis release mechanism for IL-1α is biologically well-established but the specific Rider 2011 claims about timing and cell recruitment in sterile inflammation remain unconfirmed from the primary source.

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Footnotes

Footnotes

1. doi:10.1111/imr.12621 · Dinarello CA · Immunol Rev 2017 · review · comprehensive overview of the IL-1 family (11 ligands, 10 receptors); covers IL-1α dual function (intracrine + extracellular), receptor biology, processing, and therapeutic implications · archive: failed (download failed; no OA URL found) — no-fulltext-access; claims attributed to this review are unverified against full text ↩ ↩² ↩³

2. doi:10.1073/pnas.0308705101 · Werman A et al. · PNAS 2004 · in-vitro (transfection, reporter assays, multiple cell lines including NIH/3T3, COS-7, MS1, Raw264.7) · demonstrated that pIL-1α precursor translocates to nucleus upon inflammatory stimulus (LPS, IL-1, TNF) and activates transcription from a heterologous GAL4 promoter 90-fold; the propiece (ppIL-1α) also activated >50-fold; the mature form (mIL-1α) was without activity in this system; pIL-1α activates NF-κB and AP-1 in an IL-1R-independent (intracrine) manner; NLS-deletion mutant result is from Buryskova 2004 (^buryskova2004), not this paper · archive: verified (green OA) ↩ ↩²

3. doi:10.1074/jbc.M306342200 · Buryskova M et al. · J Biol Chem 2004 · in-vitro (co-immunoprecipitation, GAL4-reporter transactivation assays, yeast two-hybrid, HEK293 and yeast) · nuclear IL-1α N-terminal propiece (IL-1NTP) physically interacts with histone acetyltransferases p300, PCAF, and Gcn5, and with adaptor protein Ada3 (SAGA/PCAF complex components); IL-1NTP integrates non-destructively into the p300-PCAF complex; transactivation requires an intact SAGA complex and cooperation with p300 (not CBP specifically); N- and C-terminal acidic helices of IL-1NTP mediate the interaction; NLS-deletion mutant (VVATN) retains association with p300 and Ada3 but loses transactivation potency · archive: verified (OA) ↩

4. doi:10.1073/pnas.0905299106 · Orjalo AV et al. · PNAS 2009 · in-vitro (HCA2 primary human foreskin fibroblasts; bleomycin-induced, replicative, oncogenic RAS^V12, and NaB-induced senescence models) · 79% of senescent cells vs 20% of presenescent cells surface-labeled for IL-1α by FACS; neutralising anti-IL-1α Ab (0.6 μg/ml) or rIL-1Ra (240 ng/ml) abrogated IL-6 and IL-8 secretion; IL-1β Ab had no effect on IL-6/IL-8; IRAK1 depletion (>90% by shRNA) prevented IL-6 secretion; IL-1α depletion reduced NF-κB (p65) and C/EBPβ DNA binding; IL-1α is the surface-bound upstream master regulator of the senescence-associated IL-6/IL-8 autocrine loop, acting through IL-1R1/IRAK1/NF-κB · archive: verified (green OA) ↩ ↩²

5. doi:10.4049/jimmunol.1102048 · Rider P et al. · J Immunol 2011 · in-vivo (mouse, sterile peritonitis model) · IL-1α and IL-1β recruit distinct myeloid cell populations and drive different phases of sterile inflammation; IL-1α is the early-phase alarmin released in sterile injury · archive: failed (download failed; publisher paywall) — no-fulltext-access; claims derived from this paper are unverified against full text ↩

6. doi:10.1084/jem.187.9.1463 · Horai R et al. · J Exp Med 1998 · in-vivo (gene-targeted mouse, Il1a-/-, Il1b-/-, Il1a/b-/-, Il1rn-/- lines; C57BL/6 × DBA/2 F1 background) · IL-1α-/- mice: viable, fertile, normal fever after turpentine; IL-1β-/- mice: fever abrogated; IL-1β (not IL-1α) required for turpentine-induced fever and glucocorticoid secretion; mutual induction: IL-1α mRNA >30-fold suppressed in IL-1β-/- brain; paper does NOT report contact hypersensitivity phenotype · archive: verified (open access via PMC) ↩