Affinage

IFNL2

Interferon lambda-2 · UniProt Q8IZJ0

Length
200 aa
Mass
22.3 kDa
Annotated
2026-06-10
23 papers in source corpus 18 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IFNL2 (IL-28A) is a secreted type III interferon that engages the IL-28R1/IL-10R2 (IL-10Rβ) receptor complex on epithelial and other cells to mount antiviral defense and shape immune responses at mucosal surfaces (PMID:16051921). Receptor engagement activates JAK-STAT (STAT1/STAT2/STAT3) together with ERK1/2, SAPK/JNK, and Akt signaling, driving expression of interferon-stimulated antiviral genes such as MxA and 2',5'-OAS and suppressing replication of diverse viruses including CMV, HCV, HSV-1, and CVB3 (PMID:16051921, PMID:16146571, PMID:21499846, PMID:25528576); this signaling is restrained by SOCS-1, which abolishes IL-28A-induced STAT1/STAT3 phosphorylation and ISG induction (PMID:15850793). Genetic ablation of Ifnl2/Ifnl3 phenocopies loss of the IFNLR receptor in controlling norovirus, reovirus, and influenza at mucosal sites, establishing IFN-λ2/λ3 as the exclusive ligands for IFNLR-mediated mucosal antiviral signaling (PMID:31462571). Beyond direct antiviral action, IL-28A shapes adaptive immunity by modulating dendritic cells—downregulating OX40L and upregulating IL-12—to drive T-bet-dependent Th1 differentiation via an IFN-γ axis (PMID:17241885, PMID:21538995), and it drives NK- and CD8+ T-cell-mediated anti-tumor immunity in an IFN-γ-dependent manner (PMID:27561689). IL-28A also promotes angiogenesis in endothelial cells through IL-10Rβ-dependent eNOS/AKT and ERK1/2 signaling with HSP70-1 as an essential downstream effector (PMID:39127098). Its transcription is positively regulated by IRF7 in intestinal barrier maintenance (PMID:39370517) and by the ATG10S isoform, which competes with IRF1 at the IFNL2 promoter (PMID:31996071).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2005 Medium

    Established that IL-28A acts through the IL-28R1/IL-10R2 receptor to activate JAK-STAT and MAPK/Akt pathways and induce antiviral ISGs, defining its core signaling axis.

    Evidence Western blot, qPCR, and CMV antiviral assay in intestinal epithelial cells

    PMID:16051921

    Open questions at the time
    • Receptor stoichiometry and ligand-binding determinants not resolved
    • Relative contribution of MAPK vs JAK-STAT to antiviral output unclear
  2. 2005 Medium

    Identified SOCS-1 as a negative regulator that shuts down IL-28A-driven STAT phosphorylation and ISG induction, placing a brake on the pathway.

    Evidence SOCS-1 overexpression with Western blot and qPCR in hepatic cell lines

    PMID:15850793

    Open questions at the time
    • Endogenous regulation by SOCS-1 not tested
    • Mechanism of SOCS-1 recruitment to the receptor not defined
  3. 2005 Medium

    Showed IL-28A suppresses HCV replication and IRES-mediated translation and synergizes with IFN-alpha, framing its therapeutic antiviral relevance.

    Evidence HCV replicon assay, IRES reporter, and combination treatment in hepatoma cells

    PMID:16146571

    Open questions at the time
    • Effector ISGs mediating HCV suppression not identified at this stage
    • Mechanism of IRES translation block unknown
  4. 2006 High

    Placed IL-28A upstream of the IFN-γ/T-bet axis in driving Th1 cytokine production, establishing an immunomodulatory role beyond direct antiviral signaling.

    Evidence IL-28A-transgenic × T-bet-deficient genetic epistasis in a Con A hepatitis model

    PMID:17241885

    Open questions at the time
    • Whether T-cell effects are cell-intrinsic or via accessory cells not fully resolved
  5. 2010 Medium

    Distinguished IL-28A from IL-29 by revealing a unique gene-repressive transcriptional signature despite shared ISG induction.

    Evidence Microarray transcriptome analysis with HCV replicon assay in hepatic cells

    PMID:21170333

    Open questions at the time
    • Mechanism of gene repression not defined
    • Functional consequence of repressed genes untested
  6. 2011 High

    Defined the dendritic-cell mechanism by which IL-28A skews Th1 over Th2/Th17 responses, linking it to IL-12 and IFN-γ in allergic airway protection.

    Evidence IL-28Rα KO mice, adoptive transfer of CD11c+ cells, and IL-12/IFN-γ neutralization

    PMID:21538995

    Open questions at the time
    • Direct DC receptor signaling events downstream of IL-28A not mapped
  7. 2011 Medium

    Showed IL-28A restricts HSV-1 in neuronal cells via IL-10Rβ and selectively engages TLR/IRF7-driven antiviral programs, extending antiviral action to the nervous system.

    Evidence Anti-IL-10Rβ neutralization and HSV-1 replication/qPCR assays in neuronal cells

    PMID:21499846

    Open questions at the time
    • Only partial receptor blockade observed, suggesting additional receptor contributions
    • Mechanism of selective TLR induction unknown
  8. 2012 Medium

    Revealed context-dependent pro-tumorigenic signaling in bladder cancer where IL-28A enhances migration/invasion via NF-κB/AP-1 and MMP induction.

    Evidence Immunoblot, EMSA, and migration/invasion assays in bladder cancer cells

    PMID:22962576

    Open questions at the time
    • Reconciliation with anti-tumor effects in other tumor types unresolved
  9. 2012 Medium

    Demonstrated direct growth-suppressive and pro-apoptotic activity of IL-28A on EGFR-mutant lung cancer cells, supporting a tumor-suppressive role in this context.

    Evidence STAT1/caspase-3/7 assays, neutralizing antibody, and in vivo xenograft imaging

    PMID:23021208

    Open questions at the time
    • Determinants of EGFR-mutation selectivity not defined
  10. 2014 Medium

    Extended antiviral and cytoprotective action to viral myocarditis, where IL-28A reduces CVB3 load and apoptosis via STAT1/STAT2 and Bcl-2/BAX modulation.

    Evidence Immunoblot, TUNEL, and plaque assays in a CVB3 myocarditis model

    PMID:25528576

    Open questions at the time
    • Direct effector ISGs in cardiomyocytes not identified
  11. 2015 Medium

    Identified EPSTI1 as an IL-28A-induced ISG required for HCV restriction, linking IL-28A to a PKR-dependent antiviral effector arm.

    Evidence siRNA knockdown, overexpression, HCV replication, and PKR promoter assays

    PMID:26146465

    Open questions at the time
    • How EPSTI1 activates the PKR promoter mechanistically not resolved
  12. 2016 Medium

    Established that intratumoral IL-28A drives anti-tumor immunity through NK and CD8+ T cells in an IFN-γ-dependent, IL-12-synergistic manner.

    Evidence Immune cell depletion, IFN-γ-deficient mice, CTL and tumor growth assays

    PMID:27561689

    Open questions at the time
    • Direct vs indirect action on tumor cells not separated
  13. 2019 High

    Proved IFN-λ2/λ3 are the exclusive IFNLR ligands for mucosal antiviral defense by genocopying receptor knockout with double-ligand knockout.

    Evidence Ifnl2/3 double-KO vs Ifnlr1-KO mice across norovirus, reovirus, and influenza models

    PMID:31462571

    Open questions at the time
    • Non-redundant individual roles of IFN-λ2 vs IFN-λ3 not dissected
  14. 2020 Medium

    Defined transcriptional control of IFNL2 by the ATG10S isoform, which enters the nucleus and competes with IRF1 at the promoter to drive expression.

    Evidence Promoter deletion, DNA-IP, luciferase, mutagenesis, and co-IP with KPNA1/KPNB1/IRF1

    PMID:31996071

    Open questions at the time
    • Physiological signals controlling ATG10S generation not defined
    • Generality across cell types untested
  15. 2020 Medium

    Revealed an unexpected intracellular antiviral mechanism in which an IL-28A homotetramer binds HCV NS5A and mediates its autolysosomal degradation.

    Evidence Co-IP, deletion mapping, structural prediction, and autophagy marker assays in HepG2 cells

    PMID:32205851

    Open questions at the time
    • Structural basis of tetramerization rests partly on computational prediction
    • Relationship to canonical secreted signaling unclear
  16. 2024 High

    Established a pro-angiogenic function of IL-28A through IL-10Rβ-dependent eNOS/AKT/ERK signaling with HSP70-1 as an essential effector.

    Evidence siRNA, HUVEC functional assays, KO/transgenic mice, and hind-limb ischemia model

    PMID:39127098

    Open questions at the time
    • How HSP70-1 couples to eNOS/AKT mechanistically not resolved
  17. 2024 Medium

    Placed IL-28A downstream of IRF7 in maintaining intestinal epithelial barrier integrity, with recombinant IL-28A rescuing barrier defects and colitis susceptibility.

    Evidence Irf7-KO mice, DSS colitis, and recombinant IL-28A rescue with barrier marker readouts

    PMID:39370517

    Open questions at the time
    • Direct receptor signaling restoring barrier molecules not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of IL-28A receptor binding and the distinct, non-redundant roles of IFN-λ2 versus IFN-λ3 in vivo remain unresolved.
  • No experimental structure of the IL-28A/receptor complex in the corpus
  • Tissue-specific division of labor among type III IFN ligands undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005576 extracellular region 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1643685 Disease 2
Partners
ATG10IL10RBIL28RAIRF1NS5ASOCS1

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 IL-28A (IFNL2) binds to the receptor complex IL-28R1/IL-10R2 on intestinal epithelial cells, activating ERK-1/2, SAPK/JNK MAPKs, and Akt signaling, inducing STAT1 phosphorylation, upregulating SOCS3, MxA, and 2',5'-OAS mRNA, and reducing CMV-infected cells by up to 83%. Western blot (STAT1 phosphorylation, MAPK activation), qPCR (antiviral gene expression), flow cytometry (CMV infection), cell proliferation assay American journal of physiology. Gastrointestinal and liver physiology Medium 16051921
2005 SOCS-1 overexpression completely abrogates IL-28A-induced STAT1 and STAT3 phosphorylation and abolishes IL-28A-induced mRNA expression of antiviral proteins 2',5'-OAS and MxA in hepatic cell lines, identifying SOCS-1 as a negative regulator of IL-28A signaling. Transient transfection (SOCS-1 overexpression), Western blot (STAT1/3 phosphorylation), qPCR (2',5'-OAS and MxA mRNA) Biochemical and biophysical research communications Medium 15850793
2005 IL-28A activates the JAK-STAT signaling pathway in human hepatoma cells, induces interferon-stimulated genes (ISGs) including 6-16 and 1-8U, induces HLA class I antigen expression, suppresses HCV subgenomic RNA replication in a dose-dependent manner, and synergistically enhances IFN-alpha antiviral efficacy. IL-28A also specifically suppresses HCV IRES-mediated translation. HCV RNA replicon assay, Western blot (JAK-STAT activation), qPCR (ISG expression), IRES reporter assay, combination treatment with IFN-alpha Virology journal Medium 16146571
2006 IL-28A induces Th1 cytokine production by CD4+ T lymphocytes in a T-bet-dependent manner. In IL-28A-transgenic mice, augmented Con A-induced hepatitis with elevated IFN-gamma production was suppressed by crossing with T-bet-deficient mice, placing IL-28A upstream of the IFN-gamma/T-bet signaling pathway in T-cell-mediated liver injury. Transgenic mouse generation, genetic epistasis (IL-28A-transgenic × T-bet-deficient double mutant), in vivo Con A hepatitis model, cytokine measurements, antisense oligonucleotide knockdown Gastroenterology High 17241885
2010 IL-28A activates STAT1 signaling and induces a similar set of antiviral genes as IL-29 in hepatic cells; however, unlike IL-29, IL-28A is a potent gene repressor, uniquely down-regulating 272 genes as determined by microarray analysis. Microarray transcriptome analysis, Western blot (STAT1 phosphorylation), qPCR, HCV replicon assay PloS one Medium 21170333
2011 IL-28A modulates lung CD11c+ dendritic cell function by down-regulating OX40L and up-regulating IL-12p70, thereby promoting Th1 differentiation and suppressing Th2/Th17 responses; IL-28A-mediated protection from allergic airway disease was absent after IL-12 neutralization or in IFN-gamma-deficient mice, and could be adoptively transferred by IL-28A-treated CD11c+ cells. Recombinant cytokine treatment, IL-28Rα knockout mice, adoptive transfer of CD11c+ cells, antibody neutralization (IFN-gamma, IL-12), flow cytometry, cytokine measurements EMBO molecular medicine High 21538995
2011 IL-28A inhibits HSV-1 replication in human NT2-N neurons and CHP212 neuronal cells via a mechanism partially blocked by anti-IL-10Rβ antibody; IL-28A selectively induces TLR expression and activates TLR-mediated antiviral pathways including IRF7, IFN-alpha, and IFN-alpha-stimulated antiviral genes. Neutralizing antibody (anti-IL-10Rβ), viral replication assay (HSV-1 DNA and protein quantification), qPCR (TLR and antiviral gene expression) Journal of neurovirology Medium 21499846
2012 IL-28A stimulation of bladder cancer cells activates MAPK and JAK-STAT signaling, induces NF-κB and AP-1 transcription factors, upregulates MMP-2 and MMP-9 expression, and enhances cell migration and invasion. Immunoblot, EMSA (NF-κB/AP-1 activity), real-time PCR, wound-healing/invasion assays, confocal immunofluorescence PloS one Medium 22962576
2012 IL-28A (IFN-λ2) treatment of lung cancer cells with EGFR mutations induces STAT1 phosphorylation, growth suppression, and apoptotic cell death; anti-tumor effect was confirmed in vivo in a cancer cell transplant animal model, and neutralizing antibodies to IFN-λ inhibited IL-28A-induced caspase-3/7 activity. In vitro cell viability/proliferation assay, Western blot (STAT1 phosphorylation), caspase-3/7 activity assay, neutralizing antibody, in vivo luminescent imaging in animal model Lung cancer (Amsterdam, Netherlands) Medium 23021208
2014 In CVB3-induced myocarditis, IL-28A treatment increases STAT1 and STAT2 expression, reduces viral load, and inhibits CVB3-induced apoptosis in myocardial cells with an increased Bcl-2/BAX ratio. Immunoblot (STAT1/STAT2), TUNEL assay (apoptosis), plaque assay (viral load), immunohistochemistry (Bcl-2/BAX/Caspase-3) The Brazilian journal of infectious diseases Medium 25528576
2015 EPSTI1 (epithelial-stromal interaction 1) is an IL-28A-induced ISG that is required for IL-28A-mediated inhibition of HCV replication; forced EPSTI1 expression inhibits HCV replication independently of interferon, while EPSTI1 knockdown enhances viral replication. EPSTI1 activates PKR promoter and induces PKR-dependent antiviral genes (IFN-β, IFIT1, OAS1, RNase L). siRNA knockdown, overexpression, HCV replication assay, promoter assay (PKR), qPCR Mediators of inflammation Medium 26146465
2016 Intratumoral IL-28A drives anti-tumor immunity through NK cells and CD8+ T cells; IL-28A-mediated tumor suppression is completely impaired in IFN-gamma-deficient mice, and IL-28A increases CD8+ T cell infiltration and specific CTL reactivity. IL-12 acts synergistically with IL-28A. In vivo cell depletion (NK, CD8+ T cells), IFN-gamma-deficient mice, tumor growth assay, CTL assay, immunohistochemistry Cancer gene therapy Medium 27561689
2019 Mice lacking both Ifnl2 and Ifnl3 (Ifnl2/3 double knockout) phenotypically recapitulate Ifnlr1-knockout mice in their inability to control murine norovirus, reovirus, and influenza virus at mucosal sites (intestine and lung), establishing that IFN-λ2 and IFN-λ3 are the exclusive ligands for IFNLR-mediated antiviral signaling at mucosal surfaces. Genetic knockout (Ifnl2/3 double KO mice), epistasis comparison with Ifnlr1-/- mice, viral infection models (norovirus, reovirus, influenza) Journal of virology High 31462571
2020 ATG10S (a shorter isoform of ATG10) translocates to the nucleus and binds the IFNL2 promoter at an IRF1 binding site (core motif CAAGAC), competing with IRF1 to promote IFNL2 transcription; ATG10S interacts with KPNA1/importin-α, KPNB1/importin-β, and IRF1 (shown by co-IP); knockdown of IRF1 increases ATG10S-driven IFNL2 transcription. Promoter deletion analysis, DNA immunoprecipitation, luciferase reporter assay, site-directed mutagenesis (nucleotide substitutions in core motif), co-immunoprecipitation, subcellular localization, RT-PCR, Western blot, siRNA knockdown Autophagy Medium 31996071
2020 IL-28A forms a homotetramer in cells; the first α-helix of IL-28A is required for homotetramer formation. The IL-28A homotetramer (but not monomer) binds HCV NS5A at the NS5A-ISDR region, promotes autolysosome formation, and mediates autolysosomal degradation of HCV NS5A and other HCV proteins. HCV NS5A activates incomplete autophagy by promoting ATG3/5/7/10 and LC3B but blocking autophagy flux. Co-immunoprecipitation, cell immunofluorescence, sequential deletion mutants, software structural prediction, Western blot (autophagy markers), HepG2 cell-based assays Cell death & disease Medium 32205851
2024 IL-28A promotes angiogenesis in endothelial cells via the IL-10Rβ receptor, activating eNOS/AKT and ERK1/2 signaling, inducing AP-1/NF-κB/MMP-2 network. HSP70-1 is an essential downstream effector; HSP70-1 knockdown abolishes IL-28A-induced angiogenic responses and eNOS/AKT signaling. IL-10Rβ gene ablation blocks IL-28A-induced angiogenic responses. IL-28A accelerated blood flow recovery in a hind-limb ischemia mouse model. siRNA knockdown (HSP70-1, IL-10Rβ), HUVEC proliferation/migration/invasion/tube formation assays, immunoblot, EMSA, aortic ring ex vivo assay, Matrigel plug in vivo assay, HSP70-1 KO and transgenic mice, hind-limb ischemia model, NGS transcriptomics Journal of advanced research High 39127098
2024 IRF7 promotes intestinal barrier integrity through IL-28A; Irf7-/- mice show reduced IL-28A expression and compromised barrier markers (Muc2, E-cadherin, β-catenin, Occludin). Recombinant IL-28A treatment restores these barrier molecules and rescues Irf7-/- mice from enhanced DSS-induced colitis susceptibility, placing IL-28A downstream of IRF7 in intestinal epithelial barrier maintenance. Irf7 knockout mice, DSS colitis model, recombinant IL-28A rescue experiment, qPCR/Western blot (barrier molecule expression), intestinal epithelial cell stimulation with recombinant IL-28A Journal of translational medicine Medium 39370517
2010 IL-28A does not induce CD25 or Foxp3 expression on cord blood CD4+ T cells, does not promote their proliferation, and does not induce regulatory T cell function in this cell type. Flow cytometry (CD25, Foxp3), Treg suppression assay, cell proliferation assay Immunopharmacology and immunotoxicology Low 20148705

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 IL-28A and IL-29 mediate antiproliferative and antiviral signals in intestinal epithelial cells and murine CMV infection increases colonic IL-28A expression. American journal of physiology. Gastrointestinal and liver physiology 186 16051921
2011 IL-28A (IFN-λ2) modulates lung DC function to promote Th1 immune skewing and suppress allergic airway disease. EMBO molecular medicine 182 21538995
2010 IL-28A, IL-28B, and IL-29: promising cytokines with type I interferon-like properties. Cytokine & growth factor reviews 138 20655797
2005 SOCS-1 inhibits expression of the antiviral proteins 2',5'-OAS and MxA induced by the novel interferon-lambdas IL-28A and IL-29. Biochemical and biophysical research communications 76 15850793
2010 Comparative analysis of the lambda-interferons IL-28A and IL-29 regarding their transcriptome and their antiviral properties against hepatitis C virus. PloS one 71 21170333
2005 Novel type I interferon IL-28A suppresses hepatitis C viral RNA replication. Virology journal 61 16146571
2012 Identification of pro-inflammatory cytokines associated with muscle invasive bladder cancer; the roles of IL-5, IL-20, and IL-28A. PloS one 53 22962576
2019 Disruption of Type III Interferon (IFN) Genes Ifnl2 and Ifnl3 Recapitulates Loss of the Type III IFN Receptor in the Mucosal Antiviral Response. Journal of virology 41 31462571
2012 Potential anti-tumor effect of IFN-λ2 (IL-28A) against human lung cancer cells. Lung cancer (Amsterdam, Netherlands) 38 23021208
2006 IL-28A is a key regulator of T-cell-mediated liver injury via the T-box transcription factor T-bet. Gastroenterology 35 17241885
2015 EPSTI1 Is Involved in IL-28A-Mediated Inhibition of HCV Infection. Mediators of inflammation 29 26146465
2014 Mesenchymal stem cells are efficiently transduced with adenoviruses bearing type 35-derived fibers and the transduced cells with the IL-28A gene produces cytotoxicity to lung carcinoma cells co-cultured. BMC cancer 18 25255777
2011 IL-29/IL-28A suppress HSV-1 infection of human NT2-N neurons. Journal of neurovirology 14 21499846
2024 IL-28A/IL-10Rβ axis promotes angiogenesis via eNOS/AKT signaling and AP-1/NF-κB/MMP-2 network by regulating HSP70-1 expression. Journal of advanced research 11 39127098
2022 Serum IL-28A/IFN-λ2 is linked to disease severity of COVID-19. Scientific reports 11 35361913
2016 Anti-tumor immunity elicited by direct intratumoral administration of a recombinant adenovirus expressing either IL-28A/IFN-λ2 or IL-29/IFN-λ1. Cancer gene therapy 11 27561689
2010 The effect of IL-28A on human cord blood CD4+ T cells. Immunopharmacology and immunotoxicology 6 20148705
2024 Interferon regulatory factor 7 alleviates the experimental colitis through enhancing IL-28A-mediated intestinal epithelial integrity. Journal of translational medicine 5 39370517
2012 Sequence analysis of the IL28A/IL28B inverted gene duplication that contains polymorphisms associated with treatment response in hepatitis C patients. PloS one 5 22253847
2020 A new transcription factor ATG10S activates IFNL2 transcription by binding at an IRF1 site in HepG2 cells. Autophagy 4 31996071
2014 Antiviral and myocyte protective effects of IL-28A in coxsackievirus B3-induced myocarditis. The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases 3 25528576
2024 Reduced IFNL1 and/or IFNL2, but not IFNL3 is associated with worse outcome in patients with COVID-19. Clinical and experimental immunology 1 38953458
2020 IL28A protein homotetramer structure is required for autolysosomal degradation of HCV-NS5A in vitro. Cell death & disease 1 32205851

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