Affinage

CCL3

C-C motif chemokine 3 · UniProt P10147

Length
92 aa
Mass
10.1 kDa
Annotated
2026-06-09
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCL3 (MIP-1α/LD78α) is a secreted CC chemokine that orchestrates leukocyte recruitment and inflammatory responses by signaling through the G protein-coupled receptors CCR1 and CCR5 (PMID:7505609, PMID:18941229, PMID:20870892). It was identified as a major CD8+ T cell-derived HIV-suppressive factor, blocking HIV-1, HIV-2, and SIV replication, and its non-allelic isoform LD78β shows markedly greater receptor affinity and HIV-suppressive potency owing to a proline at position 2 (PMID:8525373, PMID:10364178). In vivo, CCL3 is required for normal inflammatory responses to viral infection and drives a broad spectrum of pathologies through receptor-restricted signaling: CCR1-dependent recruitment of leukocytes underlies radiation-induced lung fibrosis, T cell-mediated hepatitis, hepatocellular carcinoma progression, and NK-cell mobilization from bone marrow, whereas CCR5-dependent signaling promotes lung metastasis and macrophage/fibroblast accumulation (PMID:7667639, PMID:18941229, PMID:16284949, PMID:20870892, PMID:15368307, PMID:18227348). Downstream of its receptors CCL3 activates PI3K/AKT and MAPK/ERK survival and migration cascades, as well as p38, JNK, NF-κB, and AMPK branches that drive MMP and VEGF-A expression in tumor cells and tight-junction disruption in gastric epithelium (PMID:12506012, PMID:26713602, PMID:24047437, PMID:38730482). CCL3 exerts cell-type-specific effects on proliferation and differentiation, suppressing hematopoietic progenitor and keratinocyte proliferation while promoting myeloid differentiation, osteoclastogenesis, and—in the aging marrow—adipogenic over osteogenic BMSC differentiation (PMID:1571537, PMID:8345211, PMID:9121122, PMID:30279500, PMID:36378535). Structurally, CCL3 self-associates into rod-shaped double-helical oligomers stabilized by glycosaminoglycan binding; polymerization buries receptor-binding sites and protects against degradation, while insulin-degrading enzyme selectively cleaves monomers and neutrophil serine proteases (cathepsin G, elastase, proteinase 3) inactivate it at defined sites (PMID:20959807, PMID:27091995, PMID:15728180, PMID:8499450). Its expression is tightly controlled transcriptionally—downstream of FGFR3/RAS-MAPK and Hippo/YAP1 signaling, with STAT1 binding the promoter directly—and post-transcriptionally through tristetraprolin-mediated destabilization of its AU-rich mRNA (PMID:21784977, PMID:16849642, PMID:38730482, PMID:38816384).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1992 High

    Established the first non-chemotactic functional role of CCL3 as a negative regulator of progenitor cell proliferation, defining it as more than an inflammatory mediator.

    Evidence In vitro CFU-S colony assays and in vivo myeloprotection after chemotherapy; in vitro clonogenic keratinocyte assays with mRNA localization to Langerhans cells

    PMID:1571537 PMID:8345211

    Open questions at the time
    • Receptor and signaling mechanism of growth inhibition not defined
    • Whether inhibition is direct or paracrine-mediated unresolved
  2. 1993 High

    Identified CCR1 as a functional GPCR for CCL3 and began characterizing its self-association behavior and promoter regulation, anchoring receptor signaling and gene control.

    Evidence Stable transfectants with cAMP/calcium readouts; analytical ultracentrifugation/CD/fluorescence on oligomeric states; promoter deletion, EMSA, and footprinting

    PMID:7505609 PMID:8474441 PMID:8499450

    Open questions at the time
    • Structural basis of oligomerization not yet resolved
    • Functional consequence of multimeric vs monomeric forms unknown at this stage
    • Identity of ICK-1 binding factors not molecularly defined
  3. 1995 High

    Defined CCL3 as a major HIV-suppressive factor and demonstrated its non-redundant requirement for antiviral inflammatory responses in vivo.

    Evidence Protein purification, neutralizing antibody blockade, recombinant inhibition of HIV/SIV; MIP-1α knockout mice in Coxsackievirus and influenza models

    PMID:7667639 PMID:8525373

    Open questions at the time
    • Receptor competition mechanism of HIV suppression not yet defined
    • Cell types mediating in vivo antiviral effect not fully resolved
  4. 1999 High

    Resolved why CCL3 isoforms differ functionally by pinpointing a single Pro-2 residue in LD78β that drives enhanced CCR5/D6 binding and HIV suppression.

    Evidence Receptor binding affinity assays, Pro-2 site-directed mutagenesis, HIV-1 suppression assays

    PMID:10364178

    Open questions at the time
    • Structural basis of Pro-2-conferred affinity not determined
    • Physiological relevance of isoform ratio in vivo unaddressed
  5. 2004 High

    Demonstrated receptor-specific roles for CCL3 in tissue pathology and dissected a novel transcriptional repression pathway, separating CCR1- and CCR5-driven effects.

    Evidence CCR1-/- and CCL3-/- mice in HCC and Con A hepatitis models with met-RANTES blockade; PGE2 pathway dissection (EP2→cAMP→EPAC→PI3K→PKB→GSK3→CDP) with siRNA

    PMID:15368307 PMID:15498767 PMID:16284949

    Open questions at the time
    • Whether CCR1 effects are direct on tumor cells or via recruited leukocytes not fully resolved
    • Generality of CDP repression across cell types unknown
  6. 2008 High

    Established CCL3-CCR5 as a driver of the metastatic tumor microenvironment and CCL3-CCR1 as a regulator of NK cell trafficking, broadening its physiological reach.

    Evidence CCL3-/- and CCR5-/- mice with bone marrow chimeras and MMP-9/HGF induction assays; NK cell subset chemotaxis and in vivo mobilization with AMD-3100

    PMID:18227348 PMID:18941229

    Open questions at the time
    • Mechanism of CXCL12 priming of NK responsiveness not molecularly defined
    • Relative contributions of stromal vs hematopoietic CCL3 sources incompletely mapped
  7. 2010 High

    Solved the structural and biophysical logic of CCL3 self-assembly, showing polymerization regulates receptor accessibility and proteolytic stability.

    Evidence X-ray crystallography, SEC/AUC, mutagenesis, monocyte arrest assays, IDE knockdown; endothelial polarized presentation by immunoelectron microscopy

    PMID:20047691 PMID:20959807

    Open questions at the time
    • In vivo significance of polymer vs monomer equilibrium not quantified
    • How polymer disassembly is regulated physiologically unknown
  8. 2011 High

    Defined post-transcriptional control of CCL3 by tristetraprolin and proved its causal role in inflammatory disease via genetic epistasis.

    Evidence TTP-bound mRNA screen and RIP in macrophages; CCL3-/-/TTP-/- double-KO rescue of arthritis and atherosclerosis

    PMID:21784977

    Open questions at the time
    • Other ARE-binding proteins acting on CCL3 mRNA not surveyed
    • Tissue specificity of TTP-mediated control not detailed
  9. 2016 High

    Refined the structural understanding of CCL3 oligomers in complex with glycosaminoglycans, revealing a distinct GAG-binding groove and conformational plasticity of the N-terminus.

    Evidence X-ray crystallography of GAG-bound oligomers, biophysical analyses, mutagenesis

    PMID:27091995

    Open questions at the time
    • In vivo role of GAG-anchored oligomers in haptotactic gradients not directly tested
    • Link between N-terminal conformation and receptor signaling not established
  10. 2018 Medium

    Clarified the hematopoietic function of CCL3 by showing it promotes myeloid lineage differentiation and constrains the HSPC pool independently of the bone marrow niche.

    Evidence CCL3-/- mice with flow cytometry of hematopoietic compartments and microenvironment analysis

    PMID:30279500

    Open questions at the time
    • Cell-intrinsic vs extrinsic mechanism of differentiation promotion unresolved
    • Receptor mediating this effect not identified
  11. 2024 High

    Identified direct transcriptional control of CCL3 by STAT1 and by Hippo/YAP1, completing a picture of multilayered upstream regulation linked to epithelial and skeletal pathology.

    Evidence ChIP of STAT1 at the CCL3 promoter with JAK1-STAT1→CCL3→p38 tight-junction disruption rescue; Yap1 conditional KO/AAV5 overexpression with promoter blocking in disc degeneration model

    PMID:38730482 PMID:38816384

    Open questions at the time
    • Interplay between STAT1, YAP1, FGFR3/RAS, and CDP at the promoter not integrated
    • Context determining which upstream input dominates not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the structural state of CCL3 (monomer, oligomer, GAG-bound polymer) is dynamically tuned in vivo to bias CCR1 versus CCR5 engagement and select among its many context-specific outcomes remains unresolved.
  • No in vivo measurement linking oligomeric state to receptor choice
  • Determinants of CCR1 vs CCR5 selectivity in a given tissue undefined
  • Unified model integrating proteolysis, polymerization, and transcriptional control absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 3
Localization
GO:0005576 extracellular region 2
Pathway
R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4
Partners
CCR1CCR5IDEZFP36

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 CCL3 (MIP-1α), along with RANTES and MIP-1β, was identified as a major HIV-suppressive factor produced by CD8+ T cells. Purified proteins from CD8+ T cell supernatants showed sequence identity with RANTES and MIP-1α; neutralizing antibody combinations against all three chemokines completely blocked HIV-SF activity; recombinant CCL3 caused dose-dependent inhibition of HIV-1, HIV-2, and SIV replication. Protein purification from cell supernatants, sequence identity, neutralizing antibody blockade, recombinant protein inhibition assay Science High 8525373
1995 MIP-1α (CCL3) is required in vivo for a normal inflammatory response to viral infection. CCL3-knockout mice were resistant to Coxsackievirus-induced myocarditis and showed reduced pneumonitis and delayed clearance of influenza virus, with no overt hematopoietic abnormalities. Gene knockout mouse model (MIP-1α -/- mice), viral infection models (Coxsackievirus, influenza), histological and virological assessment Science High 7667639
1993 HM145 (later identified as CCR1) is a functional G protein-coupled receptor for LD78 (CCL3), as demonstrated by decreased cAMP accumulation and calcium influx in stable transfectants expressing HM145 upon LD78 stimulation. Stable transfection, cAMP accumulation assay, calcium influx measurement International immunology High 7505609
2010 CCL3 (MIP-1α) and CCL4 (MIP-1β) form rod-shaped, double-helical polymers via a polymerization process. Polymerization buries receptor-binding sites of CCL3, so depolymerization mutations enhance CCL3's ability to arrest monocytes on activated endothelium. Insulin-degrading enzyme (IDE) selectively degrades monomeric CCL3, and decreased IDE expression leads to elevated CCL3 in microglial cells. X-ray crystallography, biophysical analysis (SEC, AUC), mathematical modelling, mutagenesis, monocyte arrest assay, proteomics, IDE knockdown in microglial cells The EMBO journal High 20959807
2016 Crystal structures of CCL3 oligomers bound to glycosaminoglycans (GAGs) revealed that CCL3 forms rod-shaped double-helical oligomers and uses a distinct GAG-binding groove formed by residues from two partially buried BBXB motifs. An alternative CCL3 oligomer structure showed that conformational changes in the N-termini profoundly alter surface properties and dimer-dimer interactions, affecting both GAG binding and oligomerization. X-ray crystallography, biophysical analyses, mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 27091995
1999 LD78β (MIP-1αP), a non-allelic isoform of CCL3 (LD78α), has ~6-fold enhanced binding affinity to CCR5 and ~15–20-fold enhanced affinity to the D6 receptor compared to LD78α. A proline residue at position 2 of LD78β is responsible for this enhanced receptor binding activity and markedly higher HIV-1 suppressive activity. Receptor binding affinity assays, site-directed mutagenesis (Pro-2 substitution), HIV-1 suppression assays The Journal of biological chemistry High 10364178
2005 Neutrophil-derived serine proteases (cathepsin G, elastase, proteinase 3) cleave CCL3 isoforms LD78β and LD78α at specific sites (Thr16-Ser17, Phe24-Ile25, Tyr28-Phe29, Thr31-Ser32), with cathepsin G preferentially cleaving at Phe24-Ile25 and Tyr28-Phe29 and elastase/proteinase 3 at Thr16-Ser17 and Thr31-Ser32. Proteolysis of LD78β results in loss of chemotactic activity. In vitro protease cleavage assay, mass spectrometry and peptide sequencing, serine protease inhibitor studies, neutrophil lysates from Papillon-Lefèvre syndrome patients, chemotaxis assay The Journal of biological chemistry High 15728180
1993 The LD78α gene promoter contains multiple positive and negative regulatory elements. A negative regulatory element (ICK-1) is a binding site for both positive (ICK-1B) and negative (ICK-1A) transcriptional factors; an ICK-1-like element is shared with IL-3 and GM-CSF gene promoters, suggesting common transcriptional control among hematopoietic growth factors. Promoter deletion analysis, electrophoretic mobility shift assay (EMSA), in vivo footprinting, transfection/reporter assays Molecular and cellular biology Medium 8474441
2004 PGE2 inhibits CCL3 and CCL4 expression in dendritic cells via a novel signaling pathway: EP-2 → cAMP → EPAC → PI3-kinase → PKB → GSK-3, leading to increased DNA binding of the CCAAT displacement protein (CDP), a transcriptional repressor; CDP knockdown with siRNA directly linked CDP to CCL3/4 transcription. Pharmacological inhibitors of each pathway step, siRNA knockdown of CDP, EMSA/DNA binding assays, ELISA for CCL3/4 protein The Journal of biological chemistry High 15498767
2011 Tristetraprolin (TTP) directly binds CCL3 mRNA via conserved AU-rich elements and destabilizes it. TTP-/- macrophages produce elevated LPS-induced CCL3; CCL3-/-/TTP-/- double knockout mice show significant improvement in inflammatory arthritis and reduced aortic plaque formation compared with TTP-/- single knockouts. TTP-bound mRNA screen in activated macrophages, RIP/RNA binding assay, TTP-/- and CCL3-/-/TTP-/- double-KO mice, histological and functional assessments Journal of immunology High 21784977
2002 CCL3 (MIP-1α) acts as a growth, survival, and chemotactic factor in multiple myeloma (MM) cells by activating both the AKT/PKB and the MAPK/ERK pathways; PI3-K inhibitors blocked AKT activation but not ERK activation, indicating no cross-talk between these two CCL3-dependent signaling branches in MM cells. Chemotaxis assay, cell proliferation/survival assays, pathway inhibitors (PI3-K inhibitors), Western blot for pAKT and pERK Blood Medium 12506012
2008 The CCL3-CCR5 axis regulates intratumoral accumulation of macrophages, granulocytes, and fibroblasts and promotes neovascularization in lung metastasis. CCL3 stimulates macrophages to express MMP-9 and fibroblasts to express HGF via CCR5. CCL3-/- and CCR5-/- mice showed markedly reduced lung metastasis foci, reduced intratumoral leukocyte/fibroblast accumulation, and reduced MMP-9 and HGF expression. CCL3-/- and CCR5-/- mice, bone marrow chimera, in vitro CCL3 stimulation assays, immunohistochemistry Journal of immunology High 18941229
2010 CCL3 (MIP-1α) released by activated endothelial cells binds preferentially to the apical surface of cytokine-activated human brain microvessel endothelial cells (HBMEC). In resting HBMEC, CCL3 is minimally expressed, but TNF-α, IL-1β, LPS and TNF-α/IFN-γ significantly upregulate its expression and release; the polarized apical surface presentation of CCL3 after cytokine treatment was established by immunoelectron microscopy. Primary HBMEC culture, ELISA, immunocytochemistry, immunoelectron microscopy Journal of neuroinflammation Medium 20047691
2006 CCL3 (MIP-1α) expression is downstream of FGFR3 and RAS-MAPK signaling in multiple myeloma. FGFR3 inhibitors and FGFR3-specific siRNA downregulated MIP-1α promoter activity, gene expression, and protein secretion; ERK1 inhibition also downregulated MIP-1α in cells with RAS mutations, placing CCL3 downstream of FGFR3→RAS→MAPK. FGFR3 kinase inhibitors, FGFR3 siRNA, FGF ligand stimulation, promoter assays, gene expression profiling, ERK1 inhibition Blood High 16849642
2004 CCL3 (MIP-1α) and its receptor CCR1 are required for hepatocellular carcinoma progression. CCR1- and CCL3-deficient mice showed markedly reduced tumor foci and reduced tumor angiogenesis, associated with decreased intratumoral Kupffer cell accumulation and reduced MMP-9 gene expression. CCR1-/- and CCL3-/- mice in DEN-induced and HBs antigen splenocyte transfer HCC models, immunohistochemistry, gene expression analysis International journal of cancer High 16284949
2010 CCL3 (via CCR1) mediates the thoracic radiation-induced lung inflammation and fibrosis. Irradiated CCL3-/- mice or CCR1-/- mice did not develop lung inflammation, fibrosis, or decline in lung function seen in wild-type mice; pharmacologic CCR1 inhibition also prevented these outcomes. By contrast, CCR5-/- mice were not protected. CCL3-/-, CCR1-/-, CCR5-/- mice, pharmacological CCR1 inhibitor, hydroxyproline assay, flow cytometry, lung function measurement American journal of respiratory cell and molecular biology High 20870892
2004 CCL3 deficiency (MIP-1α-/-) attenuates T cell-mediated hepatitis by reducing recruitment of CCR1-expressing CD4+ T cells to the liver, with consequent reduction in hepatic IFN-γ production. Pharmacological dual CCR1/CCR5 blockade with met-RANTES also reduced hepatic injury and CD4+ T cell liver infiltration. CCL3-/- mice, con A hepatitis model, flow cytometry, met-RANTES pharmacological blockade, biochemical and histological liver injury assessment European journal of immunology High 15368307
2008 CCL3 selectively mobilizes mature NK (mNK) cells from the bone marrow into the periphery by acting through CCR1, and inhibits CXCL12-mediated mNK cell retention in vitro. pNK cells migrate to CCL3 only after CXCL12 priming, while immature NK cells (iNK) lack CCR1 and do not respond to CCL3. Mouse bone marrow NK cell subset characterization, in vitro chemotaxis assays, in vivo CCL3 and CXCR4 antagonist (AMD-3100) administration, flow cytometry Blood Medium 18227348
1992 CCL3/SCI/MIP-1α inhibits proliferation of primitive hematopoietic stem cell progenitors (CFU-S day 12 and day 8) in vitro in a dose-dependent manner and reduces CFU-S compartment cycling in vivo, providing myeloprotection after chemotherapy as shown by improved neutrophil recovery kinetics. In vitro CFU-S colony-forming assay, in vivo mouse bone marrow regeneration models, neutrophil recovery kinetics Blood High 1571537
1993 Recombinant LD78 protein in solution forms soluble heterogeneous multimeric complexes (100–>250 kDa) from an 8-kDa monomer; defined homogeneous monomer and tetramer forms can be prepared and display distinct conformational properties, as determined by analytical ultracentrifugation, circular dichroism, and fluorescence spectroscopy. Analytical ultracentrifugation, circular dichroism, fluorescence spectroscopy Biochemistry Medium 8499450
1992 MIP-1α (LD78/SCI) inhibits proliferation of clonogenic epidermal keratinocytes in vitro, and MIP-1α mRNA is present in epidermal Langerhans cells but not in keratinocytes, suggesting a paracrine growth inhibitory role in keratopoiesis. In vitro clonogenic keratinocyte proliferation assay with recombinant MIP-1α, Northern blot/in situ hybridization for mRNA localization The Journal of investigative dermatology Medium 8345211
1994 MIP-1α modulates spermatogenesis stage-specifically: it increases DNA synthesis in primitive type A2-4 spermatogonia and premeiotic cells, while inhibiting DNA synthesis in more differentiated intermediate and type B spermatogonia. An anti-MIP-1α antibody cross-reacts with a 15 kDa protein expressed at every spermatogenic stage. In vitro stage-specific DNA synthesis assay with recombinant MIP-1α, immunohistochemistry with anti-MIP-1α antibody Molecular and cellular endocrinology Medium 8187954
1997 MIP-1α (LD78) promotes osteoclastogenesis on calcified matrices in the absence of osteotropic hormones and is expressed by osteoblasts at bone-remodeling sites and eosinophilic myelocytes in human bone marrow, suggesting a role in bone remodeling. In situ hybridization, immunohistochemistry with monoclonal antibody, in vitro osteoclastogenesis on calcified matrices Laboratory investigation Medium 9121122
2013 In EBV-infected B cells (LCLs), LMP1-mediated JNK activation is responsible for upregulation of CCL3 and CCL4. Autocrine CCL3 and CCL4 are required for LCL survival and proliferation, as shRNA knockdown or neutralizing antibodies against CCL3/CCL4 suppressed cell proliferation and induced apoptosis. Cytokine antibody arrays, JNK inhibitor, shRNA knockdown, neutralizing antibodies, apoptosis assays Journal of virology Medium 23760235
2016 CCL3 promotes VEGF-A expression in osteosarcoma cells via activation of JNK, ERK, and p38 MAPK pathways, with each pathway inhibitor abolishing CCL3-induced VEGF-A upregulation. CCL3 also reduces miR-374b expression, and miR-374b mimic reverses CCL3-promoted VEGF-A expression and angiogenesis in vitro and in vivo. Kinase inhibitors (JNK, ERK, p38), miR-374b mimic transfection, endothelial progenitor cell migration/tube formation assays, mouse xenograft model Oncotarget Medium 26713602
2016 Elevated CCL3 in the leukemic environment suppresses erythropoiesis via CCR1-mediated p38 phosphorylation and subsequent GATA1 downregulation. CCR1 antagonist partially recovered erythroid colony yield; knockdown of CCL3 attenuated leukemic progression and alleviated anemia. Cytokine array, colony-forming cell assay, CCR1 antagonist, Western blot for p38/GATA1, CCL3 knockdown in AML mouse model Leukemia Medium 27109512
2009 Intracerebroventricularly administered CCL3 (MIP-1α) induces fever that is independent of LPS signaling cascade (PFPF, ET-1) but is dependent on CRF: a non-selective CRF receptor antagonist (α-helical CRF9-41) reduced CCL3-induced fever, while bosentan (ET receptor antagonist) did not. Anti-CCL3 antibody abolished CCL3-induced fever but did not affect LPS-induced fever. Intracerebroventricular injection, pharmacological antagonists (anti-CCL3 antibody, bosentan, α-helical CRF9-41), temperature measurement in rats Brain research Medium 19285486
2013 CCL3 stimulates human chondrosarcoma cell migration and MMP-2 expression via CCR5, AMPK, p38 MAPK, and NF-κB signaling pathways. Inhibitors or inactive mutants of AMPK, p38, and NF-κB abolished CCL3-induced MMP-2 expression and migration; MMP-2 siRNA or inhibitor blocked CCL3-induced migration. CCR5 knockdown, pharmacological inhibitors and dominant-negative mutants of AMPK/p38/NF-κB, MMP-2 siRNA, migration assay Cell communication and signaling Medium 24047437
2018 CCL3-/- mice exhibit loss of mature myeloid populations in peripheral blood while myeloid progenitors and HSPCs are increased, with unchanged bone marrow microenvironmental cell populations. This demonstrates that CCL3 promotes myeloid lineage differentiation and regulates HSPC pool size independently of the bone marrow microenvironment. CCL3-/- mice, flow cytometry of hematopoietic compartments, bone marrow microenvironment analysis Scientific reports Medium 30279500
2022 Docetaxel (DTX) induces CCL3 expression in macrophages and cancer cells by relieving CREB-mediated repression of the CCL3 promoter via ROS accumulation. DTX-induced CCL3 then promotes proinflammatory macrophage polarization via the CCL3-CCR5-p38/IRF5 signaling pathway, which subsequently facilitates macrophage phagocytosis of breast cancer cells. Ccl3-KO mice, macrophage depletion, RNA sequencing, CREB inhibitor, ROS measurement, CCR5 and p38/IRF5 pathway analysis, phagocytosis assay Journal for immunotherapy of cancer Medium 35613826
2024 H. pylori infection stimulates macrophages to secrete CCL3 via the JAK1-STAT1 pathway (with STAT1 identified as a direct transcription factor for the CCL3 promoter by ChIP assay). CCL3 then damages gastric epithelial tight junctions by activating P38 phosphorylation; neutralizing anti-CCL3 antibody or CCL3 receptor inhibitor restored tight junction integrity. RT-qPCR, Western blot, ELISA, dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), transepithelial electrical resistance, immunofluorescence, in vivo mouse CCL3 injection Cell communication and signaling High 38730482
2024 In cartilage endplate chondrocytes under abnormal mechanical stress, Hippo signaling activation suppresses YAP1, which in turn de-represses the CCL3 promoter, leading to CCL3 release that recruits osteoclasts and promotes endplate remodeling. YAP1 overexpression (via AAV5) inhibited CCL3 transcription by blocking its promoter, reversing endplate remodeling and disc degeneration. Transcriptome sequencing, Yap1 conditional knockout and overexpression (AAV5), lumbar spine instability mouse model, in vitro stress experiments Bone research Medium 38816384
2023 CCL3 in the aging bone marrow microenvironment promotes adipogenic differentiation of BMSCs via activation of STAT3 → C/EBPα, with a positive feedback loop where C/EBPα directly binds the CCL3 promoter (facilitated by DNA hypomethylation) to further activate CCL3 expression. CCL3 also inhibits osteogenic differentiation by blocking β-catenin activity through ERK-activated DKK1 upregulation. In vivo CCL3 deletion or neutralization rescued bone loss and marrow adiposity in aged mice. Antibody array, Ccl3-/- mice, in vivo neutralizing antibody treatment, BMSC differentiation assays, ChIP, Western blot for STAT3/C/EBPα/β-catenin/DKK1/ERK JCI insight High 36378535
2012 CCL3 and its receptor CCR5 are required for maintenance (but not initiation) of chronic pelvic pain in experimental autoimmune prostatitis (EAP). CCL3-/- mice showed resistance to maintenance of pelvic pain while CCR5-/- mice did not, indicating CCL3 acts through a CCR5-independent mechanism for pain maintenance. CCL3-/-, CCR5-/-, CCR2-/- mice, neutralizing antibodies, bone marrow reconstitution, von Frey and thermal pain assays American journal of physiology - regulatory, integrative and comparative physiology Medium 22814670

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science (New York, N.Y.) 2552 8525373
1995 Requirement of MIP-1 alpha for an inflammatory response to viral infection. Science (New York, N.Y.) 515 7667639
2015 Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 439 25762141
1997 A novel human CC chemokine PARC that is most homologous to macrophage-inflammatory protein-1 alpha/LD78 alpha and chemotactic for T lymphocytes, but not for monocytes. Journal of immunology (Baltimore, Md. : 1950) 200 9233607
2002 Macrophage inflammatory protein 1-alpha (MIP-1 alpha ) triggers migration and signaling cascades mediating survival and proliferation in multiple myeloma (MM) cells. Blood 184 12506012
1992 Demonstration of stem cell inhibition and myeloprotective effects of SCI/rhMIP1 alpha in vivo. Blood 177 1571537
1996 The role of MIP-1 alpha in inflammation and hematopoiesis. Journal of leukocyte biology 172 8558069
1997 Release of RANTES, MIP-1 alpha, and MCP-1 into asthmatic airways following endobronchial allergen challenge. American journal of respiratory and critical care medicine 165 9372648
1995 Role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in acute lung injury in rats. Journal of immunology (Baltimore, Md. : 1950) 144 7722328
1993 Molecular cloning of cDNAs encoding a LD78 receptor and putative leukocyte chemotactic peptide receptors. International immunology 142 7505609
1998 Cytokine induction of MIP-1 alpha and MIP-1 beta in human fetal microglia. Journal of immunology (Baltimore, Md. : 1950) 140 9570566
2010 Regulation of CCL2 and CCL3 expression in human brain endothelial cells by cytokines and lipopolysaccharide. Journal of neuroinflammation 138 20047691
2010 Polymerization of MIP-1 chemokine (CCL3 and CCL4) and clearance of MIP-1 by insulin-degrading enzyme. The EMBO journal 138 20959807
2008 CCL3-CCR5 axis regulates intratumoral accumulation of leukocytes and fibroblasts and promotes angiogenesis in murine lung metastasis process. Journal of immunology (Baltimore, Md. : 1950) 138 18941229
2017 Chemokines as adjuvants for immunotherapy: implications for immune activation with CCL3. Expert review of clinical immunology 124 28965431
1990 Structures of human genes coding for cytokine LD78 and their expression. Molecular and cellular biology 117 1694014
2010 CCL3 (MIP-1α) plasma levels and the risk for disease progression in chronic lymphocytic leukemia. Blood 111 21115978
1999 LD78beta, a non-allelic variant of human MIP-1alpha (LD78alpha), has enhanced receptor interactions and potent HIV suppressive activity. The Journal of biological chemistry 110 10364178
2008 CCL3 and CXCL12 regulate trafficking of mouse bone marrow NK cell subsets. Blood 96 18227348
2007 Sodium channel expression and the molecular pathophysiology of pain after SCI. Progress in brain research 86 17618978
2016 CCL3 promotes angiogenesis by dysregulation of miR-374b/ VEGF-A axis in human osteosarcoma cells. Oncotarget 85 26713602
2020 CCL3 Signaling in the Tumor Microenvironment. Advances in experimental medicine and biology 83 32060842
2014 Neuroinflammatory contributions to pain after SCI: roles for central glial mechanisms and nociceptor-mediated host defense. Experimental neurology 83 25017887
2006 Essential contribution of a chemokine, CCL3, and its receptor, CCR1, to hepatocellular carcinoma progression. International journal of cancer 83 16284949
2008 TNF-alpha blockage in a mouse model of SCI: evidence for improved outcome. Shock (Augusta, Ga.) 78 17621255
1997 Macrophage inflammatory protein-1 alpha (LD78) expressed in human bone marrow: its role in regulation of hematopoiesis and osteoclast recruitment. Laboratory investigation; a journal of technical methods and pathology 77 9121122
2020 CCL3-CCR5 axis contributes to progression of esophageal squamous cell carcinoma by promoting cell migration and invasion via Akt and ERK pathways. Laboratory investigation; a journal of technical methods and pathology 71 32457351
2004 A novel signaling pathway mediates the inhibition of CCL3/4 expression by prostaglandin E2. The Journal of biological chemistry 70 15498767
2020 CCL3 contributes to secondary damage after spinal cord injury. Journal of neuroinflammation 67 33246483
2013 Leukocyte-specific CCL3 deficiency inhibits atherosclerotic lesion development by affecting neutrophil accumulation. Arteriosclerosis, thrombosis, and vascular biology 67 23288165
2011 Targeting microvasculature for neuroprotection after SCI. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 67 21360237
2016 Structural basis for oligomerization and glycosaminoglycan binding of CCL5 and CCL3. Proceedings of the National Academy of Sciences of the United States of America 66 27091995
2012 CCL2 and CCL3 are essential mediators of pelvic pain in experimental autoimmune prostatitis. American journal of physiology. Regulatory, integrative and comparative physiology 66 22814670
2004 CCL3/MIP-1alpha is pro-inflammatory in murine T cell-mediated hepatitis by recruiting CCR1-expressing CD4(+) T cells to the liver. European journal of immunology 66 15368307
2022 Ccl3 enhances docetaxel chemosensitivity in breast cancer by triggering proinflammatory macrophage polarization. Journal for immunotherapy of cancer 65 35613826
2014 Role of macrophage inflammatory protein (MIP)-1α/CCL3 in leukemogenesis. Molecular & cellular oncology 63 27308309
2006 MIP-1alpha (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma. Blood 59 16849642
2020 CCL3/CCR1 mediates CD14+CD16- circulating monocyte recruitment in knee osteoarthritis progression. Osteoarthritis and cartilage 56 32006659
2014 Increased levels of soluble interleukin-6 receptor and CCL3 in COPD sputum. Respiratory research 55 25183374
1991 Genomic structure of murine macrophage inflammatory protein-1 alpha and conservation of potential regulatory sequences with a human homolog, LD78. Journal of immunology (Baltimore, Md. : 1950) 55 2033269
2011 Zinc finger protein tristetraprolin interacts with CCL3 mRNA and regulates tissue inflammation. Journal of immunology (Baltimore, Md. : 1950) 54 21784977
2010 The chemokine, CCL3, and its receptor, CCR1, mediate thoracic radiation-induced pulmonary fibrosis. American journal of respiratory cell and molecular biology 54 20870892
2005 Superoxide dismutase 1 overexpression reduces MCP-1 and MIP-1 alpha expression after transient focal cerebral ischemia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 52 15829914
1989 Synthesis of a novel cytokine and its gene (LD78) expressions in hematopoietic fresh tumor cells and cell lines. The Journal of clinical investigation 51 2687328
2016 Role of interleukin-4, the chemokine CCL3 and its receptor CCR5 in neuropathic pain. Molecular immunology 50 27522478
2005 Proteolysis of macrophage inflammatory protein-1alpha isoforms LD78beta and LD78alpha by neutrophil-derived serine proteases. The Journal of biological chemistry 49 15728180
2005 Expression of the beta chemokines CCL3, CCL4, CCL5 and their receptors in idiopathic inflammatory myopathies. Neuropathology and applied neurobiology 45 15634233
1992 Biological and structural properties of MIP-1 alpha expressed in yeast. Cytokine 45 1617159
2017 Relevance of CCL3/CCR5 axis in oral carcinogenesis. Oncotarget 41 28881626
1993 Hemopoietic stem cell inhibitor (SCI/MIP-1 alpha) also inhibits clonogenic epidermal keratinocyte proliferation. The Journal of investigative dermatology 41 8345211
1997 MIP-1 alpha contributes to the anticryptococcal delayed-type hypersensitivity reaction and protection against Cryptococcus neoformans. Journal of leukocyte biology 40 9021919
2018 The Chemokine CCL3 Regulates Myeloid Differentiation and Hematopoietic Stem Cell Numbers. Scientific reports 39 30279500
2010 Cardiovascular disease, SCI and exercise: unique risks and focused countermeasures. Disability and rehabilitation 38 20524925
2001 MIP-1 alpha and MIP-1 beta induction by dengue virus. Journal of medical virology 38 11536240
2024 Lumbar instability remodels cartilage endplate to induce intervertebral disc degeneration by recruiting osteoclasts via Hippo-CCL3 signaling. Bone research 37 38816384
2013 AMP-activated protein kinase activation mediates CCL3-induced cell migration and matrix metalloproteinase-2 expression in human chondrosarcoma. Cell communication and signaling : CCS 37 24047437
1998 Directed selection of MIP-1 alpha neutralizing CCR5 antibodies from a phage display human antibody library. Nature biotechnology 36 9702779
2019 Long Non-coding RNA HOTTIP Promotes CCL3 Expression and Induces Cartilage Degradation by Sponging miR-455-3p. Frontiers in cell and developmental biology 35 31508417
1999 Chemokine PARC gene (SCYA18) generated by fusion of two MIP-1alpha/LD78alpha-like genes. Genomics 35 10049593
2016 Leukemia cell infiltration causes defective erythropoiesis partially through MIP-1α/CCL3. Leukemia 34 27109512
1993 Characterization of cytokine LD78 gene promoters: positive and negative transcriptional factors bind to a negative regulatory element common to LD78, interleukin-3, and granulocyte-macrophage colony-stimulating factor gene promoters. Molecular and cellular biology 34 8474441
2019 The effects of CCL3, CCL4, CCL19 and CCL21 as molecular adjuvants on the immune response to VAA DNA vaccine in flounder (Paralichthys olivaceus). Developmental and comparative immunology 33 31494219
1992 SCI/MIP-1 alpha: a potent stem cell inhibitor with potential roles in development. Developmental biology 31 1601173
2020 Transcription factor RUNX3 promotes CD8+ T cell recruitment by CCL3 and CCL20 in lung adenocarcinoma immune microenvironment. Journal of cellular biochemistry 29 31898342
2016 Involvement of CC Chemokine Receptor 1 and CCL3 in Acute and Chronic Inflammatory Pain in Mice. Basic & clinical pharmacology & toxicology 29 26663750
2011 Equine herpesvirus type-1 modulates CCL2, CCL3, CCL5, CXCL9, and CXCL10 chemokine expression. Veterinary immunology and immunopathology 29 21349590
2014 Serum CCL2 and CCL3 as potential biomarkers for the diagnosis of oral squamous cell carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 28 25060177
2013 Autocrine CCL3 and CCL4 induced by the oncoprotein LMP1 promote Epstein-Barr virus-triggered B cell proliferation. Journal of virology 28 23760235
2004 MIP-1 alpha and myeloma bone disease. Cancer treatment and research 28 15043189
2019 Dendritic cell targeted Ccl3- and Xcl1-fusion DNA vaccines differ in induced immune responses and optimal delivery site. Scientific reports 27 30755656
1992 Expression of stem cell inhibitor (SCI) gene in patients with bone marrow failure. Experimental hematology 27 1468544
2023 The Role of CCL3 in the Pathogenesis of Rheumatoid Arthritis. Rheumatology and therapy 26 37227653
2021 Systematic analysis of purified astrocytes after SCI unveils Zeb2os function during astrogliosis. Cell reports 26 33535036
2019 Mechanisms of Below-Level Pain Following Spinal Cord Injury (SCI). The journal of pain 26 31493490
2022 A Selective β-Catenin-Metadherin/CEACAM1-CCL3 Axis Mediates Metastatic Heterogeneity upon Tumor-Macrophage Interaction. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 25 35403834
2024 Helicobacter pylori disrupts gastric mucosal homeostasis by stimulating macrophages to secrete CCL3. Cell communication and signaling : CCS 23 38730482
2023 CCL3 secreted by hepatocytes promotes the metastasis of intrahepatic cholangiocarcinoma by VIRMA-mediated N6-methyladenosine (m6A) modification. Journal of translational medicine 23 36691046
2016 MicroRNA-146a Contributes to SCI Recovery via Regulating TRAF6 and IRAK1 Expression. BioMed research international 23 27830143
2016 Upregulation of CCL3/MIP-1alpha regulated by MAPKs and NF-kappaB mediates microglial inflammatory response in LPS-induced brain injury. Acta neurobiologiae experimentalis 23 28094821
2014 Chemokine expression of CCL2, CCL3, CCL5 and CXCL10 during early inflammatory tendon healing precedes nerve regeneration: an immunohistochemical study in the rat. Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA 23 24809505
2010 Role of CCL3/MIP-1alpha and CCL5/RANTES during acute Trypanosoma cruzi infection in rats. Microbes and infection 23 20452453
2020 Therapeutic Mechanism of Macrophage Inflammatory Protein 1 α Neutralizing Antibody (CCL3) in Clostridium difficile Infection in Mice. The Journal of infectious diseases 22 31793629
2019 RNA sequencing analysis revealed the induction of CCL3 expression in human intracranial aneurysms. Scientific reports 22 31316152
1994 MIP-1 alpha is a regulator of mitotic and meiotic DNA synthesis during spermatogenesis. Molecular and cellular endocrinology 22 8187954
2021 Recombinant Bacteroides fragilis enterotoxin-1 (rBFT-1) promotes proliferation of colorectal cancer via CCL3-related molecular pathways. Open life sciences 21 33981848
2021 PIWI-interacting RNA 57125 restrains clear cell renal cell carcinoma metastasis by downregulating CCL3 expression. Cell death discovery 21 34732692
1999 Enhanced anti-HIV-1 activity of CC-chemokine LD78beta, a non-allelic variant of MIP-1alpha/LD78alpha. FEBS letters 21 10471782
1995 Identification of MIP-1 alpha/LD78 as a monocyte chemoattractant released by the HTLV-I-transformed cell line MT4. AIDS research and human retroviruses 21 7537510
1993 Contrasting effects of rh-MIP-1 alpha and TGF-beta 1 on chronic myeloid leukemia progenitors in vitro. Stem cells (Dayton, Ohio) 21 8298472
2022 CCL3-CCR5 axis promotes cell migration and invasion of colon adenocarcinoma via Akt signaling pathway. Environmental toxicology 20 36346222
1993 T-cell chemotactic activity of cytokine LD78: a comparative study with interleukin-8, a chemotactic factor for the T-cell CD45RA+ phenotype. International archives of allergy and immunology 20 8453306
1993 Characterization of the quaternary structure and conformational properties of the human stem cell inhibitor protein LD78 in solution. Biochemistry 20 8499450
1992 Nucleotide sequence of the third cytokine LD78 gene and mapping of all three LD78 gene loci to human chromosome 17. DNA sequence : the journal of DNA sequencing and mapping 20 1296815
2022 Moderate-Intensity Treadmill Exercise Promotes mTOR-Dependent Motor Cortical Neurotrophic Factor Expression and Functional Recovery in a Murine Model of Crush Spinal Cord Injury (SCI). Molecular neurobiology 19 36385234
1997 Expression and distribution of CC chemokine macrophage inflammatory protein-1 alpha/LD78 in the human brain. Neuroreport 19 9175116
2024 The interplay of Cxcl10+/Mmp14+ monocytes and Ccl3+ neutrophils proactively mediates silica-induced pulmonary fibrosis. Journal of hazardous materials 18 38335607
2023 CCL3 in the bone marrow microenvironment causes bone loss and bone marrow adiposity in aged mice. JCI insight 18 36378535
2022 CCL3 aggravates intestinal damage in NEC by promoting macrophage chemotaxis and M1 macrophage polarization. Pediatric research 18 36550354
2009 CCL3/MIP-1 alpha is not involved in the LPS-induced fever and its pyrogenic activity depends on CRF. Brain research 18 19285486
1998 Clinical effects of human macrophage inflammatory protein-1 alpha MIP-1 alpha (LD78) administration to humans: a phase I study in cancer patients and normal healthy volunteers with the genetically engineered variant, BB-10010. European journal of cancer (Oxford, England : 1990) 18 9849450

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