CCL16

Summary

CCL16 (C-C motif chemokine ligand 16, HGNC:10614) is a protein-coding gene on chromosome 17q12, encoding C-C motif chemokine 16 (O15467). Shows chemotactic activity for lymphocytes and monocytes but not neutrophils.

This gene is one of several cytokine genes clustered on the q-arm of chromosome 17. Cytokines are a family of secreted proteins involved in immunoregulatory and inflammatory processes. The CC cytokines are proteins characterized by two adjacent cysteines. The cytokine encoded by this gene displays chemotactic activity for lymphocytes and monocytes but not for neutrophils. This cytokine also shows a potent myelosuppressive activity and suppresses proliferation of myeloid progenitor cells. The expression of this gene is upregulated by IL-10.

Source: NCBI Gene 6360 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 22 total
• MANE Select transcript: NM_004590

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10614
Approved symbol	CCL16
Name	C-C motif chemokine ligand 16
Location	17q12
Locus type	gene with protein product
Status	Approved
Aliases	NCC-4, SCYL4, LEC, HCC-4, LMC, LCC-1, CKb12, Mtn-1
Ensembl gene	ENSG00000275152
Ensembl biotype	protein_coding
OMIM	601394
Entrez	6360

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 nonsense_mediated_decay

ENST00000610493, ENST00000611905, ENST00000613642, ENST00000890728, ENST00000890729

RefSeq mRNA: 1 — MANE Select: NM_004590 NM_004590

CCDS: CCDS11303

Canonical transcript exons

ENST00000611905 — 3 exons

Exon	Start	End
ENSE00003715369	35981345	35981497
ENSE00003730134	35978143	35978263
ENSE00003730586	35976499	35977731

Expression profiles

Bgee: expression breadth broad, 97 present calls, max score 95.84.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3905 / max 158.5890, expressed in 13 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
165413	0.2226	12
165412	0.1598	11
165414	0.0081	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
liver	UBERON:0002107	95.84	gold quality
right lobe of liver	UBERON:0001114	95.81	gold quality
spleen	UBERON:0002106	69.65	gold quality
myometrium	UBERON:0001296	65.63	gold quality
endocervix	UBERON:0000458	63.48	gold quality
body of uterus	UBERON:0009853	63.40	gold quality
subcutaneous adipose tissue	UBERON:0002190	61.78	gold quality
adipose tissue	UBERON:0001013	60.35	gold quality
smooth muscle tissue	UBERON:0001135	59.28	gold quality
thoracic mammary gland	UBERON:0005200	59.14	gold quality
uterine cervix	UBERON:0000002	58.99	gold quality
omental fat pad	UBERON:0010414	58.64	gold quality
ectocervix	UBERON:0012249	58.26	gold quality
mucosa of stomach	UBERON:0001199	58.03	gold quality
vagina	UBERON:0000996	57.10	gold quality
sural nerve	UBERON:0015488	56.54	silver quality
mucosa of transverse colon	UBERON:0004991	56.17	gold quality
gall bladder	UBERON:0002110	55.83	gold quality
left coronary artery	UBERON:0001626	55.78	gold quality
lower esophagus	UBERON:0013473	55.60	gold quality
lower esophagus muscularis layer	UBERON:0035833	55.57	gold quality
right adrenal gland	UBERON:0001233	55.17	gold quality
right coronary artery	UBERON:0001625	55.12	gold quality
left uterine tube	UBERON:0001303	54.91	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	54.76	gold quality
right adrenal gland cortex	UBERON:0035827	54.70	gold quality
right lobe of thyroid gland	UBERON:0001119	53.82	gold quality
left lobe of thyroid gland	UBERON:0001120	53.79	gold quality
esophagus	UBERON:0001043	53.74	gold quality
thyroid gland	UBERON:0002046	53.54	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.61

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF

miRNA regulators (miRDB)

71 targeting CCL16, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-202-5P	99.78	67.65	991
HSA-MIR-1273H-5P	99.77	66.32	2471

Literature-anchored findings (GeneRIF, showing 13)

• Recombinant CCL16 significantly enhances the effector and the antigen-presenting function of macrophages and augments T cell lytic activity. (PMID:14525962)
• An adenoviral vector encoding human CCL16 injected into mice with pre-established mammary carcinoma induces strong antitumor response; when given before surgical excision of primary lesions, the treatment prevents metastatic spread and cures 63% of mice. (PMID:15034014)
• CCL16 induced efficient migratory responses in human and mouse eosinophils. CCL16 is a novel functional ligand for H4 and may have a role in trafficking of eosinophils. (PMID:15265943)
• CC chemokine-4 (HCC-4)/CCL16 transduces signals differently from other CCR1-dependent chemokines and may play different roles in the immune response. (PMID:16226254)
• Elevated concentrations in bronchoalveolar lavage fluid from patients with eosinophilic pneumonia (PMID:19494526)
• Low umbilical cord blood chemokine CCL16 associates with spontaneous preterm birth (PMID:21288736)
• Data show that CCL-16 gene expression was upregulated by 7.46-fold in IBS patients when compared with controls and suggest a subclinical inflammatory component underlying IBS. (PMID:21951809)
• High umbilical artery CCL16 is prominently detected in preterm preeclamptic pregnancies with severe growth restriction. (PMID:22857868)
• Single nucleotide polymorphism (SNPs) located in and around the C-C motif chemokine ligand 16 (CCL16) gene are associated with CCL16 protein levels in blood plasma, and rs80329614 is the SNP most strongly associated with CCL16 protein levels in plasma. (PMID:27357396)
• CC motif chemokine ligand 16 inhibits the progression of liver cirrhosis via inactivating hepatic stellate cells. (PMID:31948840)
• CCL16 maintains stem cell-like properties in breast cancer by activating CCR2/GSK3beta/beta-catenin/OCT4 axis. (PMID:33500726)
• Structure and Dynamics of Human Chemokine CCL16-Implications for Biological Activity. (PMID:36358937)
• Characterizing ligand-receptor interactions and unveiling the pro-tumorigenic role of CCL16-CCR1 axis in the microenvironment of hepatocellular carcinoma. (PMID:38274805)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	ccl35.2	ENSDARG00000070378
danio_rerio	ccl35.1	ENSDARG00000103466

Paralogs (26): CX3CL1 (ENSG00000006210), CCL26 (ENSG00000006606), CCL22 (ENSG00000102962), CCL17 (ENSG00000102970), CCL24 (ENSG00000106178), CCL7 (ENSG00000108688), CCL2 (ENSG00000108691), CCL8 (ENSG00000108700), CCL1 (ENSG00000108702), CCL20 (ENSG00000115009), CCL25 (ENSG00000131142), CCL21 (ENSG00000137077), XCL1 (ENSG00000143184), XCL2 (ENSG00000143185), CCL11 (ENSG00000172156), CCL19 (ENSG00000172724), CCL13 (ENSG00000181374), CCL5 (ENSG00000271503), CCL23 (ENSG00000274736), CCL4 (ENSG00000275302), CCL18 (ENSG00000275385), CCL15 (ENSG00000275718), CCL4L2 (ENSG00000276070), CCL3L3 (ENSG00000276085), CCL14 (ENSG00000276409), CCL3 (ENSG00000277632)

Protein

Protein identifiers

C-C motif chemokine 16 — O15467 (reviewed: O15467)

Alternative names: Chemokine CC-4, Chemokine LEC, IL-10-inducible chemokine, LCC-1, Liver-expressed chemokine, Lymphocyte and monocyte chemoattractant, Monotactin-1, NCC-4, Small-inducible cytokine A16

All UniProt accessions (3): O15467, A0A087WUE5, A0A087WUU4

UniProt curated annotations — full annotation on UniProt →

Function. Shows chemotactic activity for lymphocytes and monocytes but not neutrophils. Also shows potent myelosuppressive activity, suppresses proliferation of myeloid progenitor cells. Recombinant SCYA16 shows chemotactic activity for monocytes and THP-1 monocytes, but not for resting lymphocytes and neutrophils. Induces a calcium flux in THP-1 cells that were desensitized by prior expression to RANTES.

Subcellular location. Secreted.

Tissue specificity. Mainly expressed in liver, also found in spleen and thymus. Highly expressed in LPS- and IFN-gamma-activated monocytes, weakly in some lymphocytes, including natural killer cells, gamma-delta T-cells, and some T-cell clones.

Induction. By IL10/interleukin-10.

Similarity. Belongs to the intercrine beta (chemokine CC) family.

RefSeq proteins (1): NP_004581* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000827	Chemokine_CC_CS	Conserved_site
IPR001811	Chemokine_IL8-like_dom	Domain
IPR036048	Interleukin_8-like_sf	Homologous_superfamily
IPR039809	Chemokine_b/g/d	Family

Pfam: PF00048

UniProt features (11 total): strand 5, helix 2, disulfide bond 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
5LTL	X-RAY DIFFRACTION	1.45
7SCT	X-RAY DIFFRACTION	1.84
8FK9	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15467-F1	79.62	0.52

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 (2): 37–60, 38–76

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-380108	Chemokine receptors bind chemokines
R-HSA-418594	G alpha (i) signalling events
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-388396	GPCR downstream signalling
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 121 (showing top): GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, MORF_RAD51L3, GOBP_CELL_CELL_SIGNALING, GOBP_LEUKOCYTE_CHEMOTAXIS, GOBP_TAXIS, GOBP_LEUKOCYTE_MIGRATION, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, MORF_IL4, GOBP_GRANULOCYTE_MIGRATION

GO Biological Process (12): chemotaxis (GO:0006935), inflammatory response (GO:0006954), cell communication (GO:0007154), cell-cell signaling (GO:0007267), positive regulation of cell migration (GO:0030335), eosinophil chemotaxis (GO:0048245), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), chemokine-mediated signaling pathway (GO:0070098), immune response (GO:0006955), signal transduction (GO:0007165), positive chemotaxis (GO:0050918), cell chemotaxis (GO:0060326)

GO Molecular Function (5): chemokine activity (GO:0008009), chemoattractant activity (GO:0042056), CCR chemokine receptor binding (GO:0048020), cytokine activity (GO:0005125), protein binding (GO:0005515)

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

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by GPCR	2
Peptide ligand-binding receptors	1
GPCR downstream signalling	1
Signal Transduction	1
GPCR ligand binding	1
Class A/1 (Rhodopsin-like receptors)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
cell communication	2
signaling	2
cell migration	2
chemotaxis	2
chemokine receptor binding	2
receptor ligand activity	2
response to chemical	1
taxis	1
defense response	1
regulation of cell migration	1
positive regulation of cell motility	1
granulocyte chemotaxis	1
eosinophil migration	1
antimicrobial humoral response	1
G protein-coupled receptor signaling pathway	1
cytokine-mediated signaling pathway	1
cellular response to chemokine	1
immune system process	1
response to stimulus	1
regulation of cellular process	1
cellular response to stimulus	1
cellular response to chemical stimulus	1
cytokine activity	1
cell chemotaxis	1
positive chemotaxis	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

596 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCL16	CCR1	P32246	991
CCL16	CCR5	P51681	966
CCL16	CCR2	P41597	961
CCL16	CCR8	P51685	916
CCL16	A0A0J9YW77	A0A0J9YW77	839
CCL16	CXCR5	P32302	808
CCL16	CXCL17	Q6UXB2	786
CCL16	CXCR2	P25025	660
CCL16	CCR3	P51677	629
CCL16	CCL23	P55773	609
CCL16	CXCL6	P80162	599
CCL16	ACKR2	O00590	593
CCL16	RARA	P10276	580
CCL16	CCL1	P22362	570
CCL16	CCRL2	O00421	558

IntAct

8 interactions, top by confidence:

A	B	Type	Score
CCL16	CCL5	psi-mi:“MI:0407”(direct interaction)	0.560
CCL16	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
ECE1	CCL16	psi-mi:“MI:0915”(physical association)	0.370
CCL16	USP9Y	psi-mi:“MI:0914”(association)	0.350
CCL16	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): CCL16 (Two-hybrid), CCL5 (Reconstituted Complex), MKNK1 (Affinity Capture-MS), TRIM68 (Affinity Capture-MS), TUBB8 (Affinity Capture-MS), GPD1L (Affinity Capture-MS), USP48 (Affinity Capture-MS), USP9Y (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4INB9, A9QWP9, B0R191, K7XWG4, O00175, O15467, O35903, O43927, O55038, O62812, O70460, P02775, P02778, P10146, P10148, P10720, P14844, P17515, P18340, P22362, P26894, P27784, P28292, P41324, P43030, P47992, P47993, P48298, P48973, P49113, P50228, P51672, P79255, P80325, P97545, P97885, Q07325, Q08782, Q2KIQ8, Q5KSV9

Diamond homologs: F5HET8, O00175, O00585, O15467, O35188, O55145, P10147, P10148, P13236, P13500, P14097, P14844, P16619, P27784, P28291, P28292, P42831, P46632, P48298, P50229, P50230, P51670, P52203, P55773, P55774, P61274, P61275, P78423, P80075, P80098, P80343, P97545, Q09141, Q16627, Q16663, Q17QA1, Q5I1Z0, Q5RA36, Q64H35, Q68A92

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	16
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

526 predictions. Top by Δscore:

Variant	Effect	Δscore
17:35981337:GGACT:G	donor_loss	1.0000
17:35981338:GACTC:G	donor_loss	1.0000
17:35981339:ACTC:A	donor_loss	1.0000
17:35981340:CT:C	donor_loss	1.0000
17:35981341:TCA:T	donor_loss	1.0000
17:35981342:CAC:C	donor_loss	1.0000
17:35981343:A:AC	donor_gain	1.0000
17:35981343:A:T	donor_loss	1.0000
17:35981344:C:CT	donor_gain	1.0000
17:35981344:CT:C	donor_gain	1.0000
17:35981344:CTTGG:C	donor_gain	1.0000
17:35977727:CGAAG:C	acceptor_gain	0.9900
17:35977729:AAGC:A	acceptor_loss	0.9900
17:35977730:AGCT:A	acceptor_loss	0.9900
17:35977732:C:CC	acceptor_gain	0.9900
17:35977732:C:T	acceptor_loss	0.9900
17:35977733:T:G	acceptor_loss	0.9900
17:35981344:CTT:C	donor_gain	0.9900
17:35981344:CTTG:C	donor_gain	0.9900
17:35977730:AG:A	acceptor_gain	0.9800
17:35978261:CTT:C	acceptor_gain	0.9800
17:35978503:G:A	donor_gain	0.9800
17:35981336:TGGAC:T	donor_loss	0.9800
17:35977631:T:TA	donor_gain	0.9700
17:35977728:GAAG:G	acceptor_gain	0.9700
17:35981408:CGGAG:C	donor_gain	0.9700
17:35978141:A:AC	donor_gain	0.9600
17:35978142:C:CC	donor_gain	0.9600
17:35977735:C:CT	acceptor_gain	0.9500
17:35981420:T:TA	donor_gain	0.9500

AlphaMissense

770 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:35977680:C:A	W83C	0.975
17:35977680:C:G	W83C	0.975
17:35977702:C:G	C76S	0.972
17:35977703:A:T	C76S	0.972
17:35977703:A:G	C76R	0.965
17:35978180:A:C	Y54D	0.959
17:35977711:C:G	R73P	0.955
17:35978162:A:G	C60R	0.953
17:35978203:A:G	L46S	0.948
17:35978161:C:G	C60S	0.947
17:35978162:A:T	C60S	0.947
17:35977678:A:T	V84D	0.946
17:35977729:A:G	F67S	0.942
17:35977701:G:C	C76W	0.941
17:35977702:C:T	C76Y	0.938
17:35978227:C:G	C38S	0.938
17:35978228:A:T	C38S	0.938
17:35978228:A:G	C38R	0.934
17:35978160:A:C	C60W	0.933
17:35978149:G:T	A64E	0.928
17:35977703:A:C	C76G	0.922
17:35978161:C:T	C60Y	0.919
17:35978150:C:G	A64P	0.915
17:35978226:G:C	C38W	0.909
17:35977702:C:A	C76F	0.907
17:35978161:C:A	C60F	0.907
17:35978188:A:T	V51E	0.901
17:35978231:A:G	C37R	0.898
17:35977729:A:C	F67C	0.891
17:35978227:C:T	C38Y	0.888

dbSNP variants (sampled 300 via entrez): RS1000332769 (17:35981779 C>A,T), RS1000448614 (17:35981540 A>G), RS1000906777 (17:35977505 C>T), RS1000942137 (17:35983481 T>A), RS1001334744 (17:35980627 C>T), RS1001980873 (17:35982179 C>T), RS1002337052 (17:35979098 A>G), RS1002351360 (17:35982380 C>A), RS1002464864 (17:35976402 C>T), RS1002840325 (17:35983298 A>G), RS1003370385 (17:35981122 T>C), RS1003413896 (17:35977516 A>G), RS1004035230 (17:35982430 A>T), RS1005861881 (17:35977895 C>A,G,T), RS1005918347 (17:35982443 C>T)

Disease associations

OMIM: gene MIM:601394 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005023_49	Initial pursuit acceleration	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008434	initial pursuit acceleration

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	5
methyleugenol	decreases expression	1
arsenite	decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
CGP 52608	increases reaction, affects binding	1
2-palmitoylglycerol	increases expression	1
Dimethyl Sulfoxide	affects expression	1
Estradiol	affects expression	1
N-Nitrosopyrrolidine	decreases expression	1
Nicotine	decreases expression	1
Quercetin	decreases expression	1
Valproic Acid	decreases expression	1
Vanadium	decreases expression	1
2-Naphthylamine	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases expression, increases methylation	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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