IFNL2

Summary

IFNL2 (interferon lambda 2, HGNC:18364) is a protein-coding gene on chromosome 19q13.2, encoding Interferon lambda-2 (Q8IZJ0). Cytokine with antiviral, antitumour and immunomodulatory activities.

This gene encodes a cytokine distantly related to type I interferons and the IL-10 family. This gene, interleukin 28B (IL28B), and interleukin 29 (IL29) are three closely related cytokine genes that form a cytokine gene cluster on a chromosomal region mapped to 19q13. Expression of the cytokines encoded by the three genes can be induced by viral infection. All three cytokines have been shown to interact with a heterodimeric class II cytokine receptor that consists of interleukin 10 receptor, beta (IL10RB) and interleukin 28 receptor, alpha (IL28RA).

Source: NCBI Gene 282616 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 45 total
• MANE Select transcript: NM_172138

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18364
Approved symbol	IFNL2
Name	interferon lambda 2
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	IL-28A
Ensembl gene	ENSG00000183709
Ensembl biotype	protein_coding
OMIM	607401
Entrez	282616

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000331982

RefSeq mRNA: 1 — MANE Select: NM_172138 NM_172138

CCDS: CCDS42567

Canonical transcript exons

ENST00000331982 — 6 exons

Exon	Start	End
ENSE00002216556	39268396	39268578
ENSE00002303526	39269915	39270188
ENSE00002311774	39268677	39268858
ENSE00002441331	39269152	39269229
ENSE00002500436	39269488	39269637
ENSE00002528025	39269738	39269821

Expression profiles

Bgee: expression breadth broad, 14 present calls, max score 99.22.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2503 / max 247.1288, expressed in 16 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175694	0.2503	16

Top tissues by expression

228 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	99.22	gold quality
mucosa of paranasal sinus	UBERON:0005030	78.86	gold quality
epithelium of nasopharynx	UBERON:0001951	74.39	silver quality
superficial temporal artery	UBERON:0001614	68.54	gold quality
cardia of stomach	UBERON:0001162	59.84	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	59.54	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	57.88	gold quality
sperm	CL:0000019	56.90	gold quality
jejunal mucosa	UBERON:0000399	55.83	gold quality
subthalamic nucleus	UBERON:0001906	54.53	gold quality
lateral globus pallidus	UBERON:0002476	54.28	gold quality
jejunum	UBERON:0002115	53.19	gold quality
ventral tegmental area	UBERON:0002691	52.94	gold quality
quadriceps femoris	UBERON:0001377	51.75	gold quality
oocyte	CL:0000023	51.71	gold quality
dorsal plus ventral thalamus	UBERON:0001897	51.51	gold quality
vastus lateralis	UBERON:0001379	51.48	gold quality
lateral nuclear group of thalamus	UBERON:0002736	51.10	gold quality
amniotic fluid	UBERON:0000173	50.89	gold quality
pigmented layer of retina	UBERON:0001782	50.77	gold quality
germinal epithelium of ovary	UBERON:0001304	50.62	gold quality
pylorus	UBERON:0001166	47.12	gold quality
saphenous vein	UBERON:0007318	45.60	gold quality
gingival epithelium	UBERON:0001949	45.14	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	44.99	gold quality
skeletal muscle tissue	UBERON:0001134	44.71	gold quality
tongue	UBERON:0001723	44.14	gold quality
superior surface of tongue	UBERON:0007371	44.06	gold quality
mammary duct	UBERON:0001765	43.97	gold quality
oviduct epithelium	UBERON:0004804	43.82	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.30

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IRF7, NFKB

Literature-anchored findings (GeneRIF, showing 39)

• identified from the human genomic sequence a family of three cytokines, designated interleukin 28A (IL-28A), IL-28B and IL-29, that are distantly related to type I interferons (IFNs) and the IL-10 family (PMID:12469119)
• closely positioned genes on human chromosome 19 encode distinct but paralogous proteins, which we designate interferon-lambda1 (IFN-lambda1), IFN-lambda2 and IFN-lambda3 (PMID:12483210)
• IL-28A and IL-29 induced mRNA expression of the antiviral proteins 2’,5’-OAS and MxA was abolished by overexpression of SOCS-1 (PMID:15850793)
• we found IL-28A and IL-29 act similarly to IFNs, but are less effective generally and have activity in a more limited range of cell lines (PMID:15899585)
• IECs express functional receptors for IFN-lambdas, which mediate antiviral and antiproliferative signals in IECs, suggesting a potential for therapeutic use in certain viral infections and as (antiproliferative) anticancer therapy (PMID:16051921)
• IL-28A antiviral activity is associated with the activation of the JAK-STAT signaling pathway and expression of ISGs. (PMID:16146571)
• IFN-lambdas are thus able to generate tolerogenic DCs, an activity that could thwart IFN-beta functions (PMID:16478884)
• IFNs lambda exhibit several common features with type I IFNs: antiviral activity, antiproliferative activity and in vivo antitumour activity [review] (PMID:17367910)
• These data provide direct and compelling evidence that IFN-lambda, through both extracellular and intracellular antiviral mechanisms, inhibits HIV-1 replication in macrophages. (PMID:19193806)
• recent findings about the biology of IFN-lambdas and their pathophysiological roles in viral infection, cancer, and immune responses of the innate and adaptive arms.[review] (PMID:19304895)
• study supports that IFN-lambdas do not influence every type of cell and that membrane-associated variant IFN-lambda R1 expression is not sufficient to ensure cellular sensitivity toward these cytokines. (PMID:19798076)
• Chronic hepatitis C patients with the rs12979860 CC responder genotype may have a lower endogenous IFN response to the virus. (PMID:20235331)
• In general IL-29 serum levels exceeded IL-28A/B at least twofold, with IL-29 and IL-28A/B levels being significantly higher in carriers of the rs12979860 C allele than in TT homozygous individuals in hepatitis C (PMID:21145813)
• In contrast to IL-29, IL-28A is a potent gene repressor in patients with hepatitis C (PMID:21170333)
• IL-29/IL-28A suppress herpes simplex virus type 1 (HSV-1) infection of human NT2-N neurons. (PMID:21499846)
• This study aimed to 1) examine DNA sequences in IL28B surrounding each of the reported associated single nucleotide polymorphisms and the corresponding regions in IL28A. (PMID:22253847)
• The results show that IL-28A/IL-28AR1 dyad-induced wound healing migration requires NF-kappaB-mediated MMP-9 expression by MAPK activation. (PMID:22560878)
• p38 MAPK pathway mediates IL-28A-induced cell migration through MMP-9 expression by activating NF-kappaB and AP-1 binding motifs. (PMID:22825757)
• Plasmacytoid dendritic cells are major producers of IFN-lambda2 (a type III interferon) in response to viral stimulation. (PMID:22891284)
• Elevated expression of inflammatory cytokines (IL-5, IL-20, and IL-28A) is associated with bladder cancer development. (PMID:22962576)
• IFN-lambdas can also directly affect T cells through inhibition of the T helper 2 cell (Th2) responses. IFN-lambdas have varying immunomodulatory functions under different physiological conditions (PMID:23207147)
• IL-28 genotype was not associated with response to interferon treatment (OR for GT/GG vs. TT, 0.881 (95%CI 0.388 - 2.002); P = 0.762; OR for CT/CC vs. TT, 0.902 (95%CI 0.458 - 1.778); P = 0.766). (PMID:23652058)
• Results showed no association between genotypes and alleles of IL28A, IL28B or IL29 polymorphisms and Hepatitis C virus infection. (PMID:24269996)
• Interferon regulatory factor (IRF)-3 and -7 are the key transcriptional factors for the induction of IL-28A and IL-28B genes, whereas NF-kappaB is an additional requirement for the induction of the IL-29 gene. (PMID:24385435)
• this study provides evidence for potential IL-28A participation in Behcet’s diseaseand its value as a therapeutic agent. (PMID:24973639)
• These results show that type III interferons (IFN-lambdas) play a critical protective role in human metapneumovirus infection. (PMID:25355870)
• Studies indicate that the type III interferons (IFNs) or IFN-lambdas consists of four members: IFN-lambda1 (IL-29), IFN-lambda2 (IL28A), IFN-lambda3 (IL-28B) and IFN-lambda4. (PMID:26194286)
• NS of severe fever with thrombocytopenia syndrome virus inhibited the activity of IFN-alpha1, IFN-beta, IFN-lambda1 and IFN-lambda2 through inhibition of STAT1 phosphorylation. (PMID:26353965)
• this study shows that interleukin 28A.rs12980602 genotype could be protective against HCV infection among Egyptians (PMID:30402710)
• Serum IL-28A levels were significantly elevated in patients with sepsis compared to healthy controls. (PMID:31121287)
• A new transcription factor ATG10S activates IFNL2 transcription by binding at an IRF1 site in HepG2 cells. (PMID:31996071)
• IL28A protein homotetramer structure is required for autolysosomal degradation of HCV-NS5A in vitro. (PMID:32205851)
• Type III interferons disrupt the lung epithelial barrier upon viral recognition. (PMID:32527925)
• Interleukin-29 and interleukin-28A induce migration of neutrophils in rheumatoid arthritis. (PMID:32557259)
• Linkage of Lambda Interferons in Protection Against Severe COVID-19. (PMID:33885337)
• Congenital Zika Syndrome Is Associated With Interferon Alfa Receptor 1. (PMID:34899713)
• Serum IL-28A/IFN-lambda2 is linked to disease severity of COVID-19. (PMID:35361913)
• Assessment of serum interleukin-28 as a biomarker to predict mortality in traumatic patients with sepsis. (PMID:35816926)
• Lower level of IL-28A as a predictive index of the artificial liver support system in effective treatment of patients with HBV-ACLF. (PMID:36336888)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ifnl2	ENSMUSG00000059128
mus_musculus	Ifnl3	ENSMUSG00000060747
rattus_norvegicus		ENSRNOG00000077856
rattus_norvegicus		ENSRNOG00000082401

Paralogs (2): IFNL1 (ENSG00000182393), IFNL3 (ENSG00000197110)

Protein

Protein identifiers

Interferon lambda-2 — Q8IZJ0 (reviewed: Q8IZJ0)

Alternative names: Cytokine Zcyto20, Interleukin-28A

All UniProt accessions (1): Q8IZJ0

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine with antiviral, antitumour and immunomodulatory activities. Plays a critical role in the antiviral host defense, predominantly in the epithelial tissues. Acts as a ligand for the heterodimeric class II cytokine receptor composed of IL10RB and IFNLR1, and receptor engagement leads to the activation of the JAK/STAT signaling pathway resulting in the expression of IFN-stimulated genes (ISG), which mediate the antiviral state. Has a restricted receptor distribution and therefore restricted targets: is primarily active in epithelial cells and this cell type-selective action is because of the epithelial cell-specific expression of its receptor IFNLR1. Seems not to be essential for early virus-activated host defense in vaginal infection, but plays an important role in Toll-like receptor (TLR)-induced antiviral defense. Plays a significant role in the antiviral immune defense in the intestinal epithelium. Exerts an immunomodulatory effect by up-regulating MHC class I antigen expression.

Subcellular location. Secreted.

Induction. By viral infections or double-stranded RNA.

Similarity. Belongs to the type-III (or lambda) interferon family.

RefSeq proteins (1): NP_742150* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029177	INF_lambda	Family
IPR038326	IFN-lambda_sf	Homologous_superfamily

Pfam: PF15177

UniProt features (8 total): disulfide bond 3, sequence variant 2, signal peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZJ0-F1	84.12	0.67

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (3): 41–140, 75–173, 192–199

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8854691	Interleukin-20 family signaling

MSigDB gene sets: 56 (showing top): GOBP_CELLULAR_RESPONSE_TO_VIRUS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELL_SURFACE_RECEPTOR_SIGNALING_PATHWAY_VIA_JAK_STAT, CAGCTG_AP4_Q5, GOBP_ORGAN_OR_TISSUE_SPECIFIC_IMMUNE_RESPONSE, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, IRF1_Q6, IRF_Q6, GOBP_DEFENSE_RESPONSE_TO_VIRUS, GOMF_CYTOKINE_ACTIVITY, GOMF_SIGNALING_RECEPTOR_BINDING, ISRE_01, GOBP_RESPONSE_TO_VIRUS

GO Biological Process (7): mucosal immune response (GO:0002385), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), type III interferon-mediated signaling pathway (GO:0038196), innate immune response (GO:0045087), positive regulation of immune response (GO:0050778), defense response to virus (GO:0051607), cellular response to virus (GO:0098586)

GO Molecular Function (2): signaling receptor binding (GO:0005102), cytokine activity (GO:0005125)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signaling by Interleukins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
immune response	2
response to virus	2
organ or tissue specific immune response	1
cell surface receptor signaling pathway via STAT	1
cellular response to type III interferon	1
interferon-mediated signaling pathway	1
defense response to symbiont	1
positive regulation of immune system process	1
positive regulation of response to stimulus	1
regulation of immune response	1
defense response	1
protein binding	1
receptor ligand activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

752 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IFNL2	IFNLR1	Q8IU57	999
IFNL2	IL10RB	Q08334	982
IFNL2	IFNL3	Q8IZI9	961
IFNL2	IFNL1	Q8IU54	912
IFNL2	IL22	Q9GZX6	894
IFNL2	IFNAR1	P17181	873
IFNL2	IL10	P22301	838
IFNL2	IFNA2	P01563	819
IFNL2	JAK1	P23458	814
IFNL2	IL26	Q9NPH9	799
IFNL2	IFNB1	P01574	772
IFNL2	IFNA13	P01562	765
IFNL2	STAT1	P42224	750
IFNL2	IFNAR2	P48551	718
IFNL2	IFNE	Q86WN2	717

IntAct

4 interactions, top by confidence:

A	B	Type	Score
IFNL1	ATP2B2	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
IFNL1	CRYBB3	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): IFNL2 (Affinity Capture-MS), IFNL2 (Affinity Capture-Western), IFNL2 (Affinity Capture-MS), IFNL2 (Affinity Capture-MS)

ESM2 similar proteins: A5PJ93, A6NH21, A6QQ85, A8MVS5, B0FP48, E5RIL1, E9PY61, O75631, P0C6B2, P38574, P42701, P57785, Q08351, Q15904, Q561R0, Q5T7M4, Q63148, Q64280, Q6AZ51, Q6IEE6, Q6PRD1, Q6ZVW7, Q75VT8, Q7TN60, Q80YF6, Q864V4, Q867C0, Q8BH06, Q8BX43, Q8CHT6, Q8CJ26, Q8IZI9, Q8IZJ0, Q8K4C2, Q8K5A9, Q8N3T6, Q8N9H8, Q8NAC3, Q8NFR9, Q8R2Z0

Diamond homologs: B4ER10, Q4VK74, Q8CGK6, Q8IU54, Q8IZI9, Q8IZJ0, K9M1U5

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
IFNL2	up-regulates	IFNLR1	binding
IFNL2	up-regulates	IL10RB	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

45 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	5
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

481 predictions. Top by Δscore:

Variant	Effect	Δscore
19:39268832:GCCTT:G	donor_gain	1.0000
19:39268859:G:GG	donor_gain	1.0000
19:39269151:GGAA:G	acceptor_gain	1.0000
19:39269227:CAGGT:C	donor_loss	1.0000
19:39269228:AGG:A	donor_loss	1.0000
19:39269230:G:A	donor_loss	1.0000
19:39269231:T:A	donor_loss	1.0000
19:39269484:TCAG:T	acceptor_loss	1.0000
19:39269486:AG:A	acceptor_gain	1.0000
19:39269486:AGGT:A	acceptor_gain	1.0000
19:39269486:AGGTG:A	acceptor_gain	1.0000
19:39269487:GG:G	acceptor_gain	1.0000
19:39269487:GGT:G	acceptor_gain	1.0000
19:39269487:GGTG:G	acceptor_gain	1.0000
19:39269487:GGTGA:G	acceptor_gain	1.0000
19:39269636:GT:G	donor_gain	1.0000
19:39269638:G:GG	donor_gain	1.0000
19:39269733:CACA:C	acceptor_loss	1.0000
19:39269735:CA:C	acceptor_loss	1.0000
19:39269736:A:AC	acceptor_loss	1.0000
19:39269736:A:AG	acceptor_gain	1.0000
19:39269737:G:GG	acceptor_gain	1.0000
19:39269737:GA:G	acceptor_gain	1.0000
19:39269737:GAT:G	acceptor_gain	1.0000
19:39269737:GATC:G	acceptor_gain	1.0000
19:39269737:GATCC:G	acceptor_gain	1.0000
19:39269817:AAAAG:A	donor_gain	1.0000
19:39269818:AAAG:A	donor_gain	1.0000
19:39269819:AAG:A	donor_gain	1.0000
19:39269820:AG:A	donor_gain	1.0000

AlphaMissense

1283 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:39268835:T:C	F57L	0.943
19:39268837:T:A	F57L	0.943
19:39268837:T:G	F57L	0.943
19:39268840:G:C	K58N	0.907
19:39268840:G:T	K58N	0.907
19:39268849:A:C	K61N	0.900
19:39268849:A:T	K61N	0.900
19:39268848:A:T	K61I	0.868
19:39268802:T:C	F46L	0.852
19:39268804:C:A	F46L	0.852
19:39268804:C:G	F46L	0.852
19:39269943:T:A	V178D	0.847
19:39269791:G:C	W158C	0.846
19:39269791:G:T	W158C	0.846
19:39269977:C:A	D189E	0.842
19:39269977:C:G	D189E	0.842
19:39268836:T:C	F57S	0.841
19:39269198:T:G	F80C	0.840
19:39269953:C:A	N181K	0.838
19:39269953:C:G	N181K	0.838
19:39269976:A:C	D189A	0.833
19:39269520:G:C	E101D	0.825
19:39269520:G:T	E101D	0.825
19:39269957:T:C	F183L	0.820
19:39269959:C:A	F183L	0.820
19:39269959:C:G	F183L	0.820
19:39268844:G:C	A60P	0.818
19:39269975:G:C	D189H	0.799
19:39269976:A:T	D189V	0.796
19:39269510:T:C	L98S	0.795

dbSNP variants (sampled 300 via entrez): RS1000104618 (19:39268913 G>A,C,T), RS1002153144 (19:39270434 A>G), RS1004517984 (19:39266718 T>C), RS1004895772 (19:39267027 C>T), RS1009374057 (19:39270371 G>A,C,T), RS1011408922 (19:39267069 G>A), RS1012721050 (19:39268034 G>A), RS1013723361 (19:39269294 C>A,T), RS1015037906 (19:39266779 C>G,T), RS1016059476 (19:39267809 T>C), RS1016651857 (19:39269187 C>T), RS1017052621 (19:39269328 T>C), RS1021457248 (19:39267523 T>C), RS1022459163 (19:39268911 G>A), RS1022850115 (19:39267780 C>T)

Disease associations

OMIM: gene MIM:607401 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000485_1	Response to hepatitis C treatment	9.000000e-09
GCST000557_1	Chronic hepatitis C infection	6.000000e-09
GCST009439_25	Age-related cognitive decline (language) (slope of z-scores)	6.000000e-06
GCST009856_45	Leukocyte telomere length	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
fluorene-9-bisphenol	increases expression	1
5’-methylthioadenosine	decreases reaction, increases expression	1
mono-(2-ethylhexyl)phthalate	decreases reaction, increases expression	1
anacardic acid	decreases reaction, increases expression	1
CGP 52608	affects binding, increases reaction	1
GW 6471	decreases reaction, increases expression	1
2-chloro-5-nitrobenzanilide	decreases reaction, increases expression	1
bisphenol S	decreases methylation	1
Aripiprazole	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Cadmium	decreases expression, increases abundance	1
Diethylhexyl Phthalate	increases secretion	1
Ozone	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases methylation	1
Asbestos, Serpentine	decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.