Affinage

CCL15

C-C motif chemokine 15 · UniProt Q16663

Round 2 corrected
Length
113 aa
Mass
12.2 kDa
Annotated
2026-04-28
75 papers in source corpus 42 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCL15 is a CC chemokine that functions as a proteolytically activated chemoattractant, recruiting monocytes, neutrophils, eosinophils, and immunosuppressive myeloid cells through CCR1 (and weakly CCR3), while also exerting direct antimicrobial activity at mucosal surfaces. Full-length CCL15 circulates as a weakly active 92-amino acid precursor that is converted by neutrophil cathepsin G, elastase, and MMPs into N-terminally truncated isoforms (Δ23–28) with up to 1000-fold greater potency for CCR1-mediated calcium flux, chemotaxis, and integrin-dependent adhesion (PMID:16034099, PMID:15905581, PMID:22147696). Downstream of CCR1, CCL15 engages Gi/Go–PLC–PKCδ signaling for cell migration and a pertussis toxin-insensitive Gα14/16–JAK2–STAT3 pathway that drives NF-κB activation, ICAM-1 upregulation, CXCL8 and IL-6 induction, and MMP-9 release (PMID:11943214, PMID:23125416, PMID:23690481). In colorectal, hepatocellular, and pancreatic cancers, loss of SMAD4 or oncogenic KRAS de-represses CCL15 transcription, enabling the CCL15–CCR1 axis to recruit CCR1⁺ myeloid-derived suppressor cells, tumor-associated neutrophils, and monocytes that remodel the tumor stroma and promote metastasis (PMID:23891973, PMID:26341919, PMID:30070719, PMID:35565279).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Identification of CCL15 as a novel CC chemokine acting through CCR1 and CCR3 established its fundamental role as a leukocyte chemoattractant for monocytes, neutrophils, and lymphocytes, and revealed an unexpected capacity to suppress hematopoietic progenitor colony formation.

    Evidence Recombinant protein calcium flux, Boyden chamber chemotaxis, and colony assays using CCR1/CCR3-transfected cells across multiple independent groups

    PMID:9346309 PMID:9548457 PMID:9624581

    Open questions at the time
    • No in vivo chemotactic function demonstrated
    • Relative contribution of CCR1 vs CCR3 not resolved
    • Mechanism of colony suppression unknown
  2. 1998 High

    Gene structure analysis revealed a unique four-exon organization encoding a protein with an extra disulfide bond, and identification of alternatively spliced forms showed that N-terminal length governs receptor activation potency, raising the question of how N-terminal processing is regulated in vivo.

    Evidence cDNA cloning, Northern blot, NMR structure determination, and calcium flux/chemotaxis with N-terminal variants

    PMID:10320325 PMID:9558365 PMID:9600961

    Open questions at the time
    • Physiological protease(s) responsible for N-terminal truncation not yet identified
    • Functional significance of third disulfide bond unclear
  3. 1999 High

    CCR1 knockout mice demonstrated that CCR1 is the essential mediating receptor for CCL15-induced neutrophil responses, and cross-desensitization studies revealed ligand-specific functional outcomes through the same receptor, raising the concept of biased agonism at CCR1.

    Evidence CCR1−/− mouse neutrophils, Scatchard binding, cross-desensitization, and calcium flux assays

    PMID:10202040

    Open questions at the time
    • Structural basis for ligand-specific signaling through CCR1 unknown
    • In vivo relevance of differential CCR1 agonism not tested
  4. 2002 Medium

    Pharmacological dissection of CCL15-CCR1 signaling revealed a Gi/Go–PLC–PKCδ cascade required for chemotaxis and an NF-κB-dependent transcriptional program necessary for migration, showing that CCL15-driven motility requires de novo protein synthesis.

    Evidence Pertussis toxin, PLC/PKCδ/NF-κB inhibitors, cycloheximide, and actinomycin D treatments in CCR1-expressing HOS cells

    PMID:11943214

    Open questions at the time
    • Identity of newly synthesized proteins required for migration unknown
    • Pathway validated in single overexpression cell line only
  5. 2004 High

    Systematic chemical synthesis of N-terminal truncation mutants mapped the activation switch to removal of ~24 residues, converting weakly active full-length CCL15 into a potent CCR1 agonist, and showed the C-terminal α-helix is essential for receptor binding while the third disulfide bond is dispensable.

    Evidence Fmoc-synthesized sequential truncations and point mutants, radioligand binding, calcium flux, chemotaxis with CCR1/CCR3 transfectants

    PMID:14984572

    Open questions at the time
    • Exact receptor-contact residues not mapped
    • No co-crystal structure of CCL15–CCR1 complex
  6. 2005 High

    The identity of the activating proteases was resolved: neutrophil cathepsin G generates Δ23 and Δ26 isoforms and elastase generates Δ21, each with markedly increased chemotactic potency, establishing neutrophil-mediated proteolytic activation as the physiological mechanism for converting circulating CCL15 into an active monocyte recruiter.

    Evidence Hemofiltration, purified protease incubation, MALDI-TOF MS cleavage site mapping, calcium flux, chemotaxis, and adhesion assays; confirmed with synovial fluid from RA patients

    PMID:15905581 PMID:16034099

    Open questions at the time
    • Relative contribution of each protease in vivo not quantified
    • Whether proteolytic activation occurs in healthy vs. diseased tissue is unclear
  7. 2009 Medium

    CCL15 was found to possess direct antibacterial activity against a subset of intestinal microflora, revealing a dual innate immune function beyond leukocyte chemotaxis, with upregulation in inflammatory bowel disease indicating a role in mucosal defense.

    Evidence Recombinant CCL15 bacterial binding and killing assays, qPCR and IHC in IBD tissue

    PMID:19812544

    Open questions at the time
    • Structural basis for antimicrobial activity not determined
    • Spectrum of susceptible bacteria not fully characterized
    • Relative importance vs. other antimicrobial peptides unknown
  8. 2010 High

    The CCL15–CCR1 axis was shown to be a critical driver of colorectal cancer liver metastasis: tumor-secreted CCL15 recruits CCR1⁺ immature myeloid cells that produce MMP2/MMP9 to remodel the metastatic niche, as demonstrated by epistatic knockout of CCR1, MMP2, and MMP9 and by pharmacological CCR1 blockade.

    Evidence Mouse liver dissemination model with CCR1/MMP2/MMP9 knockout hosts, CCR1 antagonist BL5923, survival analysis

    PMID:20616008

    Open questions at the time
    • Human validation of CCR1 antagonist efficacy in metastasis not performed
    • Whether CCL15 is the sole CCR1 ligand driving recruitment in this context is unresolved
  9. 2012 High

    A second signaling arm was uncovered: CCL15–CCR1 activates STAT3 Tyr705 phosphorylation via pertussis toxin-insensitive Gα14/16 proteins, leading to STAT3 nuclear translocation, CXCL8 induction, and autocrine IL-6 amplification, distinguishing CCL15 signaling from classical Gi-only chemokine pathways.

    Evidence Subcellular fractionation, confocal microscopy, anti-IL-6 neutralization, STAT3 inhibition in THP-1 macrophages and CCR1/Gα14/16-overexpressing HEK293 cells

    PMID:23125416

    Open questions at the time
    • Gα14/16 coupling confirmed in overexpression system; stoichiometry in primary cells unknown
    • Whether Gα14/16 pathway operates in all CCR1-expressing cell types is untested
  10. 2013 High

    SMAD4 was identified as a direct transcriptional repressor of CCL15: ChIP confirmed SMAD4 binding to the CCL15 promoter enhanced by TGF-β, and SMAD4 loss in CRC de-represses CCL15, recruiting CCR1⁺ MDSCs to the invasion front and promoting liver metastasis — linking a tumor suppressor pathway directly to chemokine-mediated immune evasion.

    Evidence ChIP for SMAD4 at CCL15 promoter, TGF-β treatment, SMAD4 knockdown/overexpression, nude mouse liver metastasis model, IHC of 141 clinical specimens

    PMID:23891973 PMID:26341919

    Open questions at the time
    • Whether SMAD4 loss affects CCL15 processing in addition to transcription is unknown
    • Other SMAD4-regulated chemokines may contribute to myeloid recruitment
  11. 2013 High

    CCL15 was shown to upregulate endothelial ICAM-1 via a JAK2–STAT3 pathway with STAT3 directly binding the ICAM-1 promoter, promoting monocyte adhesion under shear stress, thereby connecting CCL15 not only to cell migration but also to firm adhesion steps in leukocyte transendothelial migration.

    Evidence ChIP for STAT3 at ICAM-1 promoter, JAK/PI3K/AKT inhibitors, monocyte adhesion under static and flow conditions

    PMID:23690481

    Open questions at the time
    • In vivo relevance of CCL15-induced ICAM-1 upregulation not confirmed
    • Contribution relative to other ICAM-1 inducers (TNF-α, IL-1β) unclear
  12. 2018 High

    In hepatocellular carcinoma, CCL15 recruits CCR1⁺CD14⁺ monocytes that express immune checkpoint molecules (PD-L1, B7-H3, TIM-3) and tolerogenic enzymes (IDO, arginase), establishing the CCL15–CCR1 axis as a driver of an immunosuppressive tumor microenvironment beyond simple myeloid cell recruitment.

    Evidence Chemokine profiling, flow cytometry phenotyping, transcriptome sequencing of tumor-infiltrating monocytes, orthotopic mouse models

    PMID:30070719

    Open questions at the time
    • Whether checkpoint blockade synergizes with CCR1 antagonism is untested
    • Causal relationship between CCL15-recruited monocytes and specific checkpoint molecule induction not fully dissected
  13. 2022 Medium

    Oncogenic KRAS was identified as an upstream activator of CCL15 expression in pancreatic cancer, with CCL15 promoting cell migration through a ROS-dependent mechanism involving p22phox, extending the list of oncogenic pathways that co-opt CCL15.

    Evidence KRAS knockdown abolishes CCL15 protein, NAC treatment and p22phox knockdown attenuate CCL15-driven migration

    PMID:35565279

    Open questions at the time
    • Whether KRAS regulation of CCL15 is transcriptional or post-transcriptional is not resolved
    • ROS–migration link lacks identification of downstream effectors
  14. 2024 High

    A CCL15–CCR1–STAT3–FTO positive feedback loop between HCC cells and cancer-associated fibroblasts was discovered: CCL15 from tumor cells activates STAT3 in CAFs to induce FTO-mediated m6A demethylation of CEBPA mRNA, driving CXCL5 secretion that feeds back to upregulate CCL15 via MDM2/P53, revealing an epitranscriptomic dimension of CCL15-mediated stromal reprogramming.

    Evidence scRNA-seq, m6A sequencing, ChIP, organoid and PDX models, neutralizing anti-CCL15 antibody

    PMID:39734010

    Open questions at the time
    • Whether anti-CCL15 antibody efficacy translates to immunocompetent models is unknown
    • FTO-dependent m6A changes on other transcripts in CAFs not characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of CCL15–CCR1 interaction (no co-crystal or cryo-EM structure exists), whether CCR1 antagonists or anti-CCL15 antibodies have therapeutic efficacy in immunocompetent cancer models, and the relative physiological importance of CCL15's antimicrobial function versus its chemotactic activity in mucosal immunity.
  • No CCL15–CCR1 structural complex resolved
  • No clinical trial data targeting the CCL15–CCR1 axis
  • In vivo contribution of CCL15 antimicrobial activity not genetically tested in humans

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 7 GO:0098631 cell adhesion mediator activity 2 GO:0090729 toxin activity 1
Localization
GO:0005576 extracellular region 6
Pathway
R-HSA-1643685 Disease 6 R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 4
Partners
CCR1CCR3CDK2FTOLZIPSMAD4STAT3

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 CCL15 (Leukotactin-1/Lkn-1) was identified as a novel CC chemokine that acts as a potent agonist at CCR1 and CCR3, inducing calcium flux and chemotaxis in neutrophils, monocytes, and lymphocytes, and suppressing colony formation by hematopoietic progenitor cells. Recombinant protein production, calcium flux assays, Boyden chamber chemotaxis assays, CCR1/CCR3-transfected cell lines, colony formation assays Journal of immunology High 9346309 9548457 9624581
1998 CCL15 (HCC-2/CKβ8) gene has a unique four-exon/three-intron structure and encodes a protein with six conserved cysteines (including two extra forming a third disulfide bond anchoring the C-terminal domain to the core), and the protein activates cells via CCR1 and CCR3 in a manner dependent on N-terminal length. Gene cloning/sequencing, Northern blot, recombinant protein production, calcium flux assays, chemotaxis assays on monocytes and eosinophils Proceedings of the National Academy of Sciences of the United States of America High 9600961
1998 Two alternatively spliced forms of CCL15 (CKβ8 and CKβ8-1, differing by 17 amino acids at the N-terminus) are both potent agonists at CCR1, chemoattracting neutrophils, monocytes, and lymphocytes, and suppressing hematopoietic progenitor colony formation, demonstrating that alternative splicing produces two active chemokines from a single gene. cDNA cloning, recombinant protein expression, receptor-binding assays, calcium flux, chemotaxis assays, colony formation assays Blood High 9558365
1999 CCL15 (Lkn-1) acts via CCR1 on human neutrophils to induce high-level calcium flux and chemotaxis, while MIP-1α acting on the same receptor produces negligible responses; CCR1-/- mouse neutrophils fail to respond to either ligand, establishing CCR1 as the mediating receptor with ligand-specific functional outcomes. CCR1 knockout mice, calcium flux assays, Scatchard binding analysis, cross-desensitization studies, chemotaxis assays Journal of immunology High 10202040
1999 The solution structure of CCL15 (HCC-2, truncated 66-aa form) was determined by NMR, revealing a monomeric chemokine fold with a triple-stranded antiparallel β-sheet covered by an α-helix; unlike most chemokines, CCL15 does not dimerize across a concentration range of 0.1 μM to 2 mM, and the third disulfide bond does not influence the relative orientation of helix and β-sheet. 1H NMR spectroscopy, restrained molecular dynamics calculations (871 experimental restraints), mutagenesis of disulfide bond Biochemistry High 10320325
2001 CCL15 circulates in human blood plasma and is encoded by mono- and bicistronic transcripts from a tandem gene arrangement with CCL14a on chromosome 17q11.2; biological activity depends on N-terminal length, with shorter isoforms being more potent CCR1 and CCR3 agonists. Hemofiltration-based isolation, chromatographic characterization, Northern blot analysis, calcium flux assays Journal of leukocyte biology Medium 11527984
2002 CCL15 (Lkn-1)-induced chemotaxis through CCR1 is transduced via Gi/Go protein, phospholipase C, and PKCδ; NF-κB is also activated downstream and required for chemotaxis, as newly synthesized proteins are needed for the migratory response. Pharmacological inhibitors (pertussis toxin, PLC inhibitor, PKCδ inhibitor, NF-κB inhibitor, cycloheximide, actinomycin D), CCR1-expressing HOS cells, chemotaxis assays, PLC and PKCδ activity assays FEBS letters Medium 11943214
2004 N-terminal truncation of CCL15 by 24 amino acid residues (Δ24-CCL15) converts the weakly active full-length form into a potent CCR1 agonist and weak CCR3 agonist; the C-terminal α-helix is essential for maintaining tertiary structure and CCR1 binding activity, while the third disulfide bond and position Y70 do not affect CCR1 interaction. Chemical synthesis of sequential N-terminal truncation and point mutants using Fmoc chemistry, calcium flux assays, receptor transfectant chemotaxis (CCR1/CCR3), radioligand binding The journal of peptide research High 14984572
2004 LZIP (a transcription factor) binds directly to CCR1 (residues 21-260 of LZIP are essential for interaction) and selectively enhances Lkn-1/CCL15-induced chemotaxis without affecting chemotaxis induced by other CCR1 ligands (MIP-1α, RANTES, HCC-4), establishing LZIP as a CCR1-interacting protein that differentially modulates CCL15-specific signaling. Yeast two-hybrid screen, mammalian two-hybrid assay, co-immunoprecipitation, domain deletion mapping, chemotaxis assays in LZIP-transfected cells FASEB journal Medium 15001559
2004 CCL15 (Lkn-1) induces MMP-9 release from macrophages and macrophage-derived foam cells in a dose-dependent manner, suggesting a role in atherosclerotic plaque destabilization. THP-1 macrophage differentiation, oxidized LDL-induced foam cell preparation, CCL15 treatment, gelatin zymography for MMP-9 Nutrition research and practice Low 20126378
2004 CCL15 (both full-length CCL15(1-92) and truncated CCL15(25-92)) stimulates chemotactic endothelial cell migration and differentiation in vitro; CCL15(25-92) is at least 100-fold more potent. This angiogenic activity is mediated via CCR1 and CCR3, as it is blocked by pertussis toxin, anti-CCR1, or anti-CCR3 antibody. CCL15(25-92) also induces aortic ring sprouting and in vivo angiogenesis in the chick chorioallantoic membrane assay. Endothelial cell chemotaxis (Boyden chamber), tube formation assay, pertussis toxin and neutralizing antibody inhibition, aortic ring assay, CAM assay FEBS letters Medium 15251437
2005 Neutrophil cathepsin G is the principal protease that proteolytically processes full-length CCL15 to N-terminally truncated isoforms (Δ23 and Δ26); neutrophil elastase generates a Δ21 isoform. The truncated Δ23 and Δ26 isoforms display significantly increased potency for calcium flux, monocyte chemotaxis, and mononuclear cell adhesion to fibronectin compared to full-length CCL15, establishing neutrophil-mediated activation of CCL15 as a mechanism for monocyte recruitment. Hemofiltration, chromatographic separation, mass spectrometry identification of cleavage products, purified cathepsin G and elastase incubation, calcium flux assays, chemotaxis assays, fibronectin adhesion assays Journal of immunology High 16034099
2005 Proinflammatory proteases (including synovial fluid proteases) cleave the N-terminal domain of CCL15, converting it from a weak to a potent CCR1 agonist (up to 1000-fold increase); N-terminally truncated CCL15 was detected at relatively high levels in synovial fluid from rheumatoid arthritis patients, suggesting in vivo activation of CCL15 during inflammation. Incubation with proinflammatory proteases and physiological fluids, N-terminal sequencing, CCR1-mediated signaling and chemotaxis assays, detection in rheumatoid arthritis synovial fluid Journal of immunology High 15905581
2005 Transcription of the CCL15 gene in monocytoid cells is regulated by AP-1 (binding at -76/-65) and NF-κB through MEK and JNK MAPK pathways; dominant negative MKK4 or JNK1 reduced PMA-induced CCL15 transcription. Luciferase reporter assays, MAPK inhibitors, dominant negative kinase expression, EMSA (AP-1 binding confirmation) Biochimica et biophysica acta Medium 16364464
2004 Two NF-κB binding sites in the CCL15 promoter (at -191/-182 and -60/-51 bp from transcription start) are both essential for PMA-induced expression in monocytoid U937 cells; mutation of either site reduces induction and proteasome inhibitor blocks PMA-induced CCL15 expression. Promoter deletion/mutation analysis with luciferase reporter, EMSA, proteasome inhibitor treatment Molecules and cells Medium 15179048
2006 In chronic renal failure (CRF), plasma CCL15 concentrations are significantly elevated and include truncated isoforms (including CCL15(12-92)); CCL15(12-92) induces stronger calcium flux, chemotactic activity, and fibronectin adhesion in monocytes than full-length CCL15(1-92), and PBMCs from CRF patients show increased sensitivity to CCL15, implicating the CCL15-CCR1 axis in CRF pathophysiology. Hemofiltration, mass spectrometry (MW 10141.3 Da confirmed), calcium flux assays, chemotaxis assays, fibronectin adhesion assays in patient-derived cells Biochemical and biophysical research communications Medium 16737685
2007 CCL15 (Lkn-1) induces LZIP expression via NF-κB in an immediate early response; NF-κB binds to the LZIP promoter specifically (confirmed by EMSA and mutation analysis), and LZIP expression via NF-κB is required for Lkn-1-induced monocyte chemotaxis. Time/dose-dependent LZIP expression assays, LZIP promoter deletion/mutation analysis, luciferase reporter, EMSA, NF-κB inhibitors, chemotaxis assays The Journal of biological chemistry Medium 17296613
2009 CCL15 (Lkn-1) induces migration of eosinophilic EoL-1 cells more potently than other CCR1 ligands; signaling is mediated through Gi/Go protein, PLC, and PKCδ activation, and CCL15 also enhances butyric acid-induced eosinophil differentiation via PKCδ after binding to CCR1. Transwell chemotaxis assays, pharmacological inhibitors (pertussis toxin, U73122/PLC inhibitor, rottlerin/PKCδ inhibitor), PKCδ activity assays, morphological differentiation assessment, EPO/MBP expression Molecular biology reports Medium 19669929
2009 Human intestinal epithelial CCL15 (and its murine homolog CCL6) displays direct antibacterial activity, binding to a subset of the intestinal microflora; expression of CCL15 is upregulated in inflammatory bowel disease, revealing a novel antimicrobial function beyond leukocyte recruitment. Bacterial binding assays, antibacterial activity assays with recombinant CCL15, qPCR of intestinal epithelium, IHC of IBD samples Mucosal immunology Medium 19812544
2010 Human colorectal cancer cells secrete CCL15 (the human ortholog of mouse CCL9) to recruit CCR1+ immature myeloid cells (CD34+Gr-1-) that produce MMP2 and MMP9 to facilitate liver metastasis; genetic loss of Ccr1, Mmp2, or Mmp9 in host mice dramatically suppresses metastatic outgrowth, and a CCR1 antagonist blocks myeloid cell accumulation and prolongs survival. Mouse liver dissemination model, CCR1/MMP2/MMP9 knockout hosts, orthotopic tumor implantation, CCR1 antagonist (BL5923) treatment, survival analysis Proceedings of the National Academy of Sciences of the United States of America High 20616008
2011 MMP processing of CCL15: MMPs and serine proteases in human synovial fluid cleave CCL15 within its unique 31-amino acid extended N-terminus; the resulting products CCL15-(25-92) and CCL15-(28-92) are stronger agonists than full-length CCL15 in calcium flux assays and monocyte migration assays (Transwell), unlike other CCL chemokines that become receptor antagonists after MMP cleavage. Incubation with synovial fluid, family-wide MMP panel (14 MMPs tested against 14 CC chemokines), MALDI-TOF-MS sequencing of 149 cleavage sites, calcium flux assays, Transwell migration assays with CCR1 transfectants and THP-1 cells The Journal of biological chemistry High 22147696
2011 CCL15 is constitutively expressed by human airway smooth muscle cells (ASMC) and is strongly upregulated by TNF-α; this upregulation is inhibited by dexamethasone, the SP-1 inhibitor mithramycin A, and the IKK-2 inhibitor AS602868. TNF-α-induced CCL15 is synergistically enhanced by IFN-γ at both transcriptional and translational levels in an NF-κB-dependent manner. Primary ASMC culture, ELISA, real-time PCR, immunofluorescence, pharmacological inhibitors (dexamethasone, mithramycin A, AS602868), cytokine treatments Clinical and experimental allergy Medium 22092970
2012 CCR1-mediated CCL15 signaling in THP-1 macrophage-like cells induces STAT3 Tyr705 phosphorylation via pertussis toxin-insensitive Gα14/16 proteins; STAT3 Tyr705-phosphorylation leads to nuclear translocation and induces CXCL8 expression, while STAT3 Ser727-phosphorylation is independent and cytosolic. CCL15 also triggers IL-6 release, which mediates STAT3 Tyr705 phosphorylation in an autocrine manner. PMA-differentiated THP-1 cells and CCR1/Gα14/16-overexpressing HEK293 cells, pertussis toxin treatment, subcellular fractionation, confocal microscopy, neutralizing anti-IL-6 antibody, STAT3 inhibition, CXCL8 ELISA Journal of immunology High 23125416
2013 Loss of SMAD4 in human colorectal cancer cells upregulates CCL15 expression; SMAD4 directly binds to the CCL15 promoter to negatively regulate transcription, and TGF-β increases SMAD4 binding to the CCL15 promoter, enhancing repression. CCL15 secreted by SMAD4-deficient CRC cells recruits CCR1+ myeloid cells (CD11b+/myeloperoxidase+/MMP9+) that promote liver metastasis. SMAD4 knockdown/overexpression in CRC lines, chromatin immunoprecipitation (ChIP) for SMAD4 at CCL15 promoter, TGF-β treatment, nude mouse liver metastasis model, IHC of 141 human metastasis specimens Gastroenterology High 23891973
2013 CCL15 stimulates hepatocellular carcinoma cell migration and invasion in an autocrine manner, as demonstrated by siRNA-mediated knockdown of CCL15 reducing invasion and migration. RT-PCR, Western blot, siRNA knockdown, cell invasion assay (Matrigel), scratch/wound healing assay, MMP-9 Western blot British journal of cancer / Chinese journal of hepatology Medium 22971284 23321514
2013 CCL15 upregulates ICAM-1 expression in endothelial cells via the JAK2/STAT3 pathway: CCL15 stimulation activates JAK2 and STAT3 phosphorylation, STAT3 binds to the ICAM-1 promoter (confirmed by ChIP and reporter assays), and JAK, PI3K, and AKT inhibitors prevent CCL15-induced ICAM-1 expression and monocyte adhesion. This signaling is predominantly mediated via CCR1. Endothelial cell CCL15 stimulation and knockdown, ICAM-1 expression (Western blot, flow cytometry), reporter assays, ChIP for STAT3 at ICAM-1 promoter, JAK/PI3K/AKT inhibitors, monocyte adhesion under static and shear-stress conditions, H/R model Journal of immunology High 23690481
2015 Loss of SMAD4 in primary colorectal cancer cells promotes CCL15 expression to recruit CCR1+ MDSCs (CD11b+, CD33+, HLA-DR-; primarily granulocytic CD15+ with some monocytic CD14+) at the tumor invasion front; CCL15-expressing tumors recruit 2.2-fold more CCR1+ cells and CCL15 knockdown in SMAD4-deficient CRC cells reduces aggressive tumor growth in an orthotopic xenograft model. SMAD4/CCL15 shRNA knockdown in CRC lines, orthotopic xenograft model, IHC and double immunofluorescence of 333 clinical specimens, ELISA for serum CCL15, MDSC phenotyping Clinical cancer research High 26341919
2015 CCL15 promotes HCC cell migration and invasion via CCR1; CCR1 shRNA knockdown inhibits CCL15-induced chemotaxis and invasion of HepG2 cells and significantly reduces the activity and expression of MMP-2 and MMP-9. CCR1 shRNA knockdown, Transwell migration/invasion assays, MMP-2/MMP-9 zymography and Western blot Tumour biology Medium 26501423
2016 CCL15 mediates migration of human bone marrow-derived mesenchymal stem cells toward HCC via CCR1 receptors on hMSCs: CCL15 knockdown in HCC cells significantly reduces hMSC homing to tumor xenografts in vivo (confirmed by histology and flow cytometry), and anti-CCL15 or anti-CCR1 blockade impairs Transwell migration of hMSCs. Cytokine array, ELISA, IHC, Transwell migration, CCL15 shRNA in HCC cells, orthotopic HCC xenograft model, intravenous hMSC delivery with histological and flow cytometric homing quantification Stem cells Medium 26763650
2016 Loss of SMAD4 promotes CCL15 expression in colorectal cancer, leading to recruitment of CCR1+ tumor-associated neutrophils (and minor granulocytic MDSCs) that facilitate lung metastasis; in a mouse model, CCL15 from SMAD4-deficient CRC cells recruits CCR1+ cells to promote metastatic activity to the lung. Mouse lung metastasis model with SMAD4-manipulated CRC cells, IHC/immunofluorescence of 107 clinical lung metastasis specimens, CCR1+ cell characterization with cell-type-specific markers Clinical cancer research High 27492974
2018 In HCC, CCL15 expression is regulated by genetic, epigenetic, and microenvironmental factors; CCL15 recruits CCR1+CD14+ monocytes to the invasive margin via the CCL15-CCR1 axis; these tumor-educated monocytes express immune checkpoint molecules (PD-L1, B7-H3, TIM-3), upregulate immune-tolerogenic enzymes (IDO, arginase), and activate STAT1/3, ERK1/2, and AKT signaling in HCC cells, promoting invasion and metastasis. Orthotopic animal models confirm CCL15-CCR1 axis drives inflammatory microenvironment enriched with CCR1+ monocytes. Chemokine expression profiling of HCC cell lines and tissues, CCL15 functional assays, flow cytometry phenotyping of CCR1+CD14+ monocytes, transcriptome sequencing of tumor-infiltrating monocytes, orthotopic mouse models Hepatology High 30070719
2020 Endothelial cell-derived CCL15 mediates fibrocyte transmigration via CCR1 on fibrocytes; overexpression of CCL15 in endothelial cells or CCR1 in fibrocytes promotes transmigration, while silencing either attenuates it, establishing the CCL15-CCR1 axis as a mechanism for fibrocyte recruitment during wound healing. Transwell co-culture system, gene chip chemokine expression profiling, CCL15 overexpression/knockdown in endothelial cells, CCR1 overexpression/knockdown in fibrocytes, fibrocyte transmigration assays Molecular medicine reports Medium 33174007
2021 CCL15 derived from eosinophils (human CCL15/CCL23, mouse CCL6) interacts with CCR1 on hematopoietic stem cells to promote eosinophil differentiation and airway inflammation; Ccl6 knockout mice show decreased eosinophilia and airway inflammation after OVA challenge, and the CCR1 antagonist BX471 reduces eosinophil differentiation. Ccl6 knockout mice, OVA challenge model, CCR1 antagonist BX471, bone marrow eosinophil differentiation assays, flow cytometry Signal transduction and targeted therapy High 33640900
2021 P1-HNF4A directly targets CCL15 as a downstream gene in gastric cancer: RNA-seq identified cytokine-cytokine receptor interaction as the most enriched pathway in P1-HNF4A-overexpressing cells, and CCL15 was confirmed as a direct transcriptional target of P1-HNF4A. HNF4A isoform overexpression, RNA-seq pathway analysis, in vitro proliferation/invasion/migration assays, murine xenograft, confirmation of CCL15 as direct target Cancer biology & medicine Low 33710810
2022 Oncogenic Kras upregulates CCL15 expression in pancreatic cancer cells; CCL15 promotes PDAC cell migration and invasion through ROS, as N-Acetyl-L-Cysteine treatment or p22phox knockdown decreases CCL15-promoted cell migration. Kras knockdown abolishes CCL15 protein expression and impedes cell migration, establishing Kras→CCL15→ROS as a migration-promoting pathway. CCL15 knockdown, CCL15 neutralization, recombinant CCL15 treatment, NAC antioxidant treatment, p22phox knockdown, Kras knockdown, cell migration and invasion assays Cancers Medium 35565279
2023 CTHRC1 upregulates CCL15 in colorectal cancer cells via TGF-β/Smad pathway to recruit tumor-associated macrophages; cytokine microarray after CTHRC1 manipulation revealed CCL15 as the regulated chemokine, and pathway analysis linked CTHRC1 to CCL15 through TGFβ activation and Smad phosphorylation. Cytokine microarray, CTHRC1 overexpression/knockdown, TGF-β/Smad pathway analysis (Western blot), macrophage chemotaxis assays, multispectral IHC, in vivo CT-26 tumor model Journal of molecular medicine Medium 37987774
2024 CCL15 secreted by HCC cells signals through CCR1 on cancer-associated fibroblasts (CAFs) to induce FTO expression via the STAT3 pathway; FTO demethylates m6A on CEBPA mRNA in CAFs, leading to CXCL5 secretion by CAFs, which activates CXCR2 on HCC cells to enhance proliferation. CXCL5 in turn upregulates CCL15 in HCC cells via MDM2/P53 modulation, creating a positive feedback loop; neutralizing anti-CCL15 antibody attenuates HCC growth in PDX and co-injection models. Single-cell RNA-seq, co-culture assays, organoid models, allograft models, m6A sequencing, RNA-seq, ChIP, PDX models, neutralizing antibody treatment Cancer letters High 39734010
2024 SPP1+ macrophages drive liver cancer stemness partly through CCL15 from liver cancer cells; CCL15 produced by HCC cells drives polarization of M0 macrophages toward an SPP1+ macrophage phenotype, establishing a positive feedback loop where SPP1+ macrophages promote tumor stemness via VTN/integrin αvβ5/AMPK/YAP1/SOX4 signaling. Single-cell RNA-seq (12 patients), co-culture assays, VTN blocking, integrin αvβ5/YAP1 inhibition, chemoresistance assays Cancer letters Medium 39216547
2025 In ESCC, CCL15 and CCR1 directly interact (confirmed by co-immunoprecipitation and immunofluorescence co-localization), and autocrine CCL15-CCR1 signaling activates the AKT/ERK1/2 pathway, leading to c-Jun phosphorylation and CDK2 transcriptional activation (c-Jun binding to CDK2 promoter confirmed by ChIP-qPCR), promoting tumor cell proliferation, migration, and invasion. Co-immunoprecipitation, immunofluorescence co-localization, lentiviral CCL15/CCR1 knockdown, recombinant CCL15 treatment, PCR array, transcription factor prediction, PPI database analysis, ChIP-qPCR for c-Jun at CDK2 promoter Journal of Cancer Medium 40740234

Source papers

Stage 0 corpus · 75 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2007 Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. The Journal of infectious diseases 223 17703412
1999 Tumor necrosis factor alpha decreases, and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone: potential regulation of the glucocorticoid receptor. The Journal of clinical endocrinology and metabolism 176 10443688
2010 Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model. Proceedings of the National Academy of Sciences of the United States of America 151 20616008
2005 Proteolytic activation of alternative CCR1 ligands in inflammation. Journal of immunology (Baltimore, Md. : 1950) 144 15905581
2018 CCL15 Recruits Suppressive Monocytes to Facilitate Immune Escape and Disease Progression in Hepatocellular Carcinoma. Hepatology (Baltimore, Md.) 124 30070719
2017 Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation. Science translational medicine 120 28381538
2015 Loss of SMAD4 Promotes Colorectal Cancer Progression by Accumulation of Myeloid-Derived Suppressor Cells through the CCL15-CCR1 Chemokine Axis. Clinical cancer research : an official journal of the American Association for Cancer Research 116 26341919
2013 Loss of SMAD4 from colorectal cancer cells promotes CCL15 expression to recruit CCR1+ myeloid cells and facilitate liver metastasis. Gastroenterology 112 23891973
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