Affinage

CCL4

C-C motif chemokine 4 · UniProt P13236

Length
92 aa
Mass
10.2 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCL4 (MIP-1β/Act-2) is a CC chemokine that directs the recruitment and adhesion of leukocytes—preferentially activated CD4+ and CD8+ T cells, monocytes, regulatory T cells, and eosinophils—during immune responses, and was identified as a major CD8+ T-cell-derived soluble factor that suppresses HIV-1, HIV-2, and SIV infection by competing for its receptor (PMID:8525373, PMID:7682337, PMID:7684437, PMID:30854716). It functions chemotactically and, when immobilized on endothelial proteoglycan, promotes T-cell adhesion to VCAM-1, positioning it for leukocyte arrest on activated endothelium (PMID:7678446, PMID:7682337, PMID:7684437). CCL4 signals principally through CCR5; binding is mediated by Phe13 immediately after the conserved CC motif and by positively charged N-loop residues Arg18, Lys19, and Arg22, with monomeric CCL4 sufficient for CCR5 binding and Ca2+-mobilizing activation (PMID:10727234, PMID:12427015). CD26/DPPIV cleaves the N-terminus to generate MIP-1β(3-69), which retains CCR5 downmodulation and HIV-entry inhibition while acquiring expanded signaling through CCR1 and CCR2b (PMID:12070155, PMID:15095403). Downstream of CCR5 in primary macrophages, CCL4 nucleates an arrestin-dependent multikinase complex of Lyn, Pyk2, and PI3K p85 at the plasma membrane that is required for chemotaxis (PMID:19620252). CCL4 (and CCL3) assemble into rod-shaped double-helical polymers whose formation depends on Pro8 and buries the receptor-binding surface; polymerization protects the chemokine from selective degradation by insulin-degrading enzyme, which cleaves only the monomeric forms (PMID:20959807, PMID:25636406). Beyond leukocyte trafficking, CCL4–CCR5 signaling drives endothelial-to-mesenchymal transition via TGF-β and disrupts blood-brain-barrier tight junctions through p38 activation and loss of ZO-1/VE-cadherin (PMID:28656247, PMID:34755124), and CCL4 expression is post-transcriptionally restrained by miR-125b (PMID:25620312). CCL4 also antagonizes CCL3-mediated suppression of myeloid progenitor colony formation and mediates regulatory T-cell recruitment to B cells and APCs (PMID:1918979, PMID:11702067).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1990 Medium

    Establishing that CCL4 acts through specific cell-surface receptors was the first step in defining it as a signaling ligand rather than a generic secreted factor.

    Evidence 125I-Act-2 radioligand equilibrium binding on activated PBLs and cell lines with blocking antiserum

    PMID:2193098

    Open questions at the time
    • Receptor identity not molecularly defined
    • Downstream signaling not addressed
  2. 1991 Medium

    The finding that CCL4 antagonizes CCL3-mediated myeloid progenitor suppression revealed that closely related MIP-1 chemokines have opposing functional outputs.

    Evidence Bone marrow colony-formation assays with recombinant murine MIP-1β/MIP-1α, pulse treatments, H-ferritin specificity controls

    PMID:1918979

    Open questions at the time
    • Receptor mediating antagonism not identified
    • Single lab, murine system
  3. 1993 High

    Defining CCL4 as a chemoattractant and adhesion-promoting factor for T-cell subsets, with proteoglycan-dependent endothelial presentation, established its core role in directing lymphocyte trafficking.

    Evidence Boyden-chamber chemotaxis on T-cell subsets, VCAM-1 adhesion assays with proteoglycan-immobilized chemokine, endothelial immunolocalization

    PMID:7678446 PMID:7682337 PMID:7684437

    Open questions at the time
    • Receptor not yet defined
    • Molecular basis of adhesion augmentation unresolved
  4. 1995 High

    Identifying CCL4 as a CD8+ T-cell-derived HIV-suppressive factor and showing it shares receptors with RANTES and MIP-1α connected chemokine receptor usage to antiviral activity.

    Evidence Purification/sequencing from CD8+ T-cell supernatants, recombinant inhibition of HIV-1/2 and SIV, antibody neutralization; cross-desensitization and competition binding versus MCP-1

    PMID:7531149 PMID:8525373

    Open questions at the time
    • Specific receptor not yet named in these studies
    • Mechanism of competition not structurally resolved
  5. 2000 High

    Mapping Phe13 and N-loop residues and showing monomeric CCL4 is competent for CCR5 binding/activation defined the molecular determinants of receptor engagement.

    Evidence NMR, analytical ultracentrifugation, CCR5 binding and Ca2+ assays in CHO cells, mutagenesis (P8A, MIP(9), Phe13 substitutions, R18/K19/R22, Y15)

    PMID:10727234 PMID:12427015

    Open questions at the time
    • Receptor-bound complex structure not determined
    • Role of oligomerization in vivo unresolved
  6. 2002 High

    Demonstrating that N-terminal truncation to MIP-1β(3-69) expands receptor specificity to CCR1/CCR2b while retaining anti-HIV CCR5 activity showed how processing reprograms CCL4 function.

    Evidence Native protein purification, mass spec, CCR5 downmodulation, HIV-entry inhibition, Ca2+ signaling via CCR1/CCR2b/CCR5

    PMID:12070155

    Open questions at the time
    • Physiological enzyme not identified in this study
    • Relative in vivo abundance of truncated form unclear
  7. 2004 Medium

    Identifying CD26/DPPIV as the protease generating MIP-1β(3-69) linked surface enzyme expression to in vivo control of CCL4 receptor specificity.

    Evidence Enzymatic cleavage assays, DPPIV inhibitory peptide blockade, correlation of CD26 surface expression with conversion in PBLs

    PMID:15095403

    Open questions at the time
    • Single lab
    • Quantitative contribution to in vivo signaling not established
  8. 2009 High

    Defining the arrestin-scaffolded Lyn/Pyk2/PI3K complex downstream of CCR5 established the intracellular machinery converting CCL4 binding into macrophage chemotaxis.

    Evidence siRNA silencing, kinase inhibition, co-localization imaging, Co-IP in primary human macrophages

    PMID:19620252

    Open questions at the time
    • Generalizability to other CCL4-responsive cells untested
    • Order of complex assembly not fully resolved
  9. 2010 High

    Discovery of double-helical CCL4 polymers and their protection from insulin-degrading enzyme revealed a structural switch controlling chemokine availability and presentation.

    Evidence Crystal structures, sedimentation/DLS, depolymerization mutants, monocyte arrest and peritoneal recruitment assays, IDE identification and microglial knockdown

    PMID:20959807

    Open questions at the time
    • In vivo trigger for polymer/monomer transition unclear
    • Physiological balance of IDE degradation versus signaling unresolved
  10. 2015 Medium

    Pinpointing Pro8 as the structural determinant of oligomerization and selective IDE degradation explained why CCL4/CCL3 but not CCL18 are IDE substrates.

    Evidence Crystal structure, SAXS, P8A mutagenesis, IDE degradation assays; plus miR-125b 3'UTR targeting of CCL4

    PMID:25620312 PMID:25636406

    Open questions at the time
    • Functional consequence of P8A oligomerization defect in vivo not tested
    • miR-125b regulation mapped in limited cell types
  11. 2021 Medium

    Showing CCL4–CCR5 disrupts endothelial junctions via p38 and drives EndMT via TGF-β extended CCL4 function from leukocyte recruitment to direct modulation of vascular barriers.

    Evidence Western blot, immunofluorescence (ZO-1, VE-cadherin, F-actin), permeability and transmigration assays in vitro and in vivo; CCR5 antagonist and TGF-β siLNA in EndMT model

    PMID:28656247 PMID:34755124

    Open questions at the time
    • Single lab per study
    • Relative contribution to disease pathology not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CCL4 polymerization, CD26-mediated truncation, and receptor selection are integrated to set context-specific responses (T-cell trafficking versus tumor, vascular, and bone microenvironments) remains unresolved.
  • No structure of CCL4 bound to CCR5
  • In vivo determinants of monomer/polymer and full-length/truncated balance unknown
  • Mechanisms beyond CCR5 in non-immune contexts incompletely defined

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 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3
Partners
CCL3CCR1CCR2BCCR5CD26IDE

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 CCL4 (MIP-1β), together with RANTES and MIP-1α, was identified as a major HIV-suppressive factor produced by CD8+ T cells. Recombinant CCL4 induced dose-dependent inhibition of HIV-1, HIV-2, and SIV infection, and neutralizing antibodies against all three chemokines completely blocked HIV-suppressive activity in CD8+ T cell supernatants. Protein purification from CD8+ T cell culture supernatants, sequence identification, recombinant protein functional assay, neutralizing antibody blockade Science High 8525373
1993 CCL4 (MIP-1β), when immobilized on proteoglycan (heparin-BSA conjugate or CD44 proteoglycan), induces T cell adhesion to VCAM-1, preferentially augmenting adhesion of CD8+ T cells. CCL4 is present on lymph node endothelium in vivo, suggesting proteoglycan-mediated presentation on endothelial surfaces. In vitro T cell adhesion assay with immobilized chemokine on proteoglycan substrates, immunolocalization of CCL4 on lymph node endothelium Nature High 7678446
1993 CCL4 (MIP-1β) acts as a potent chemoattractant for activated T lymphocytes, with preferential chemotactic activity toward CD4+ T cells, and enhances T cell binding to endothelial cell monolayers. In vitro microchemotaxis (Boyden chamber) assay with recombinant human MIP-1β on activated and resting T cell subsets; endothelial adhesion assay Science High 7682337 7684437
1993 CCL4 (MIP-1β) preferentially attracts CD4+ T lymphocytes (with some preference for naive CD45RA phenotype) in microchemotaxis assays, while CCL3 (MIP-1α) has broader lymphocyte chemoattractant activity including B cells and cytotoxic T cells. In vitro microchemotaxis assay comparing recombinant MIP-1α and MIP-1β across lymphocyte subpopulations The Journal of experimental medicine High 7682337 7684437
1991 CCL4 (MIP-1β) blocks the suppressive activity of MIP-1α on myeloid progenitor cell (BFU-E, CFU-GEMM, CFU-GM) colony formation. Pulse treatment showed CCL4 must act before or simultaneously with MIP-1α; the antagonism is specific (CCL4 does not block H-ferritin suppression). Bone marrow colony formation assay with recombinant murine MIP-1β and MIP-1α, pulse-treatment experiments, specificity controls with H-ferritin Journal of immunology Medium 1918979
1995 CCL4 (MIP-1β) elicits weak monocyte chemotaxis and minimal degranulation (N-acetyl-β-D-glucosaminidase release) compared to MCP-1 and MIP-1α. Cross-desensitization experiments using intracellular Ca2+ changes and binding competition with radiolabeled MIP-1α showed that MIP-1β shares receptors with RANTES and MIP-1α but not with MCP-1/2/3. In vitro monocyte chemotaxis, degranulation, Ca2+ flux, receptor desensitization, and radiolabeled ligand competition binding assays European journal of immunology High 7531149
2001 CCL4 is the most potent chemoattractant for CD4+CD25+ regulatory T cells produced by activated B cells and professional APCs. Depletion of CCL4 led to a deregulated humoral response and production of autoantibodies, establishing CCL4 as a mediator of regulatory T cell recruitment to B cells and APCs. Gene expression profiling to identify chemokines, chemotaxis assays, CCL4 depletion experiments, analysis of humoral immune response Nature immunology High 11702067
2000 CCL4 (MIP-1β) can function as a monomer for CCR5 binding and activation. Monomeric mutants (P8A, N-terminally truncated MIP(9)) retained CCR5 binding (Ki ~480–600 pM) and the ability to activate CCR5 (induce Ca2+ release). Phe13, the residue immediately after the conserved CC motif, is a key determinant for CCR5 binding; substitution with Tyr, Leu, Lys, or Ala reduced both binding affinity and receptor activation. NMR spectroscopy, analytical ultracentrifugation, CCR5 receptor binding assays, intracellular Ca2+ release assay in CCR5-transfected CHO cells, mutagenesis Biochemistry High 10727234
2002 The naturally occurring N-terminally truncated form of CCL4 (MIP-1β(3-69)), secreted by activated human peripheral blood lymphocytes, retains the ability to downregulate CCR5 surface expression and inhibit CCR5-mediated HIV-1 entry. Unlike full-length CCL4, MIP-1β(3-69) also triggers Ca2+ responses via CCR1 and CCR2b, indicating expanded receptor specificity upon truncation. Affinity purification of native truncated protein from lymphocyte supernatants, mass spectrometry structural confirmation, CCR5 downmodulation assay, HIV entry inhibition assay, Ca2+ signaling assays through CCR1, CCR2b, and CCR5 The Journal of biological chemistry High 12070155
2004 CD26/dipeptidyl-peptidase IV (DPPIV) cleaves full-length CCL4 (MIP-1β) at its N-terminus to generate the truncated form MIP-1β(3-69). Cleavage is blocked by DPPIV inhibitory peptides derived from HIV Tat(1-9) or TAX2-R(1-9). Kinetics of conversion in activated PBLs correlates with cell surface expression of CD26. Enzymatic cleavage assay with CD26/DPPIV, DPPIV inhibitory peptide blockade in cell culture, correlation of CD26 surface expression with conversion kinetics Journal of cellular biochemistry Medium 15095403
2002 The N-loop residues Arg18, Lys19, and Arg22 of CCL4 (MIP-1β), along with Pro21, contribute to CCR5 binding through their positive charge. Tyr15 is necessary for proper chemokine folding. Binding determinants are arranged on one surface of the protein. Correlation between binding affinity and functional potency in Ca2+ assays confirms these residues are essential for CCR5 interaction. Site-directed mutagenesis, NMR spectroscopy (folding analysis), CCR5 receptor binding assay, Ca2+ mobilization functional assay Biochemistry High 12427015
2010 CCL4 (MIP-1β) and CCL3 (MIP-1α) form rod-shaped, double-helical high-molecular-weight polymers as revealed by crystal structures. Polymerization buries receptor-binding sites, and depolymerization mutations enhance CCL3/CCL4 ability to arrest monocytes on activated endothelium but render them ineffective in mouse peritoneal cell recruitment. Insulin-degrading enzyme (IDE) selectively degrades monomeric CCL4/CCL3 but not polymers; decreased IDE expression leads to elevated CCL4 levels in microglial cells. Crystal structure determination, biophysical analyses (sedimentation, DLS), mathematical modeling, depolymerization mutagenesis, monocyte arrest assays, peritoneal cell recruitment assay, proteomic identification of IDE, IDE knockdown in microglial cells The EMBO journal High 20959807
2015 Crystal structure of CCL4 shows that Pro8, conserved in CCL4 and CCL3, is critical for oligomerization. The P8A mutation in CCL4 stabilizes a type 1 β-turn at the N-terminus, preventing dimerization by a mechanism distinct from that in CCL3. IDE degrades CCL3 and CCL4 but not CCL18 (which lacks Pro8), providing a structural basis for selective degradation. Crystal structure determination, small-angle X-ray scattering, mutagenesis (P8A), IDE degradation assays Journal of molecular biology High 25636406
2009 CCL4 (MIP-1β) signaling through CCR5 in primary human macrophages requires an arrestin-dependent multi-kinase complex. CCR5 stimulation by CCL4 triggers Pyk2 and PI3K p85 translocation from cytoplasm to colocalize with Lyn at the plasma membrane, forming a multimolecular complex. Arrestins are recruited into this complex; arrestin knockdown impairs complex formation and abolishes macrophage chemotaxis toward CCL4. siRNA gene silencing, pharmacological kinase inhibition, co-localization imaging, Co-IP/complex formation assays in primary human macrophages Journal of leukocyte biology High 19620252
1990 Cell surface receptors for CCL4 (Act-2) were identified on activated peripheral blood lymphocytes and multiple cell lines (MT-2, HL60, HeLa, K562). The equilibrium dissociation constant (Kd) is 3–12 nM. A blocking polyclonal antiserum was developed that prevents Act-2 receptor binding. 125I-labeled Act-2 radioligand binding assay, equilibrium binding analysis (Kd determination), blocking antiserum development The Journal of experimental medicine Medium 2193098
2013 In prostate tumorigenesis, macrophage androgen receptor (AR) upregulates CCL4 secretion, which activates STAT3 in epithelial cells, promoting epithelial-to-mesenchymal transition and downregulation of p53/PTEN. CCL4-neutralizing antibody blocked macrophage-induced tumorigenic signaling, and an AR degradation enhancer (ASC-J9) reduced CCL4 expression and xenograft tumor growth in vivo. Macrophage-epithelial cell co-culture tumorigenesis model, CCL4 neutralizing antibody, AR degradation enhancer treatment, xenograft in vivo model, PTEN+/- macrophage AR knockout mice Cancer research Medium 23878190
2006 CCL4 promotes trophoblast migration at the feto-maternal interface. CCR1 and CCR3 (CCL4 receptors) are expressed on extravillous trophoblasts. Trophoblast migration occurred in response to CCL4 in migration assays, and this was attenuated by neutralizing antibodies to CCL4 in endometrial cell-conditioned media. Immunolocalization of chemokine receptors in human implantation sites, RT-PCR for receptor expression, trophoblast cell line migration assay, neutralizing antibody inhibition Biology of reproduction Medium 16452465
2015 miR-125b negatively regulates CCL4 expression in human immune cells (monocytes, naïve CD8 T cells) by targeting the 3'UTR seed sequence of CCL4 mRNA. shRNA knockdown of miR-125b increased CCL4 protein, while transfection of miR-125b reduced CCL4 mRNA and protein following stimulation. Reduced miR-125b in old adults correlates with elevated CCL4. shRNA knockdown of miR-125b in primary human immune cells, miR-125b overexpression by transfection, 3'UTR seed sequence validation, intracellular CCL4 protein measurement Aging cell Medium 25620312
2017 CCL4 secreted by M1 macrophage-derived foam cells induces endothelial-to-mesenchymal transition (EndMT) via CCR5, upregulating TGF-β expression, which increases endothelial permeability and monocyte adhesion. Anti-CCL4 antibody abolished EndMT; CCR5 antagonist and TGF-β knockdown reversed CCL4-induced EndMT. Protein array to identify CCL4, ELISA, anti-CCL4 antibody neutralization, CCR5 antagonist treatment, TGF-β siRNA knockdown, permeability assay, monocyte adhesion assay International journal of molecular medicine Medium 28656247
2021 CCL4 signals through CCR5 in blood-brain barrier endothelial cells to cause p38 phosphorylation, actin stress fiber formation, junctional ZO-1 reduction (~60% within 60 min), VE-cadherin internalisation, increased paracellular permeability in vitro and in vivo, and enhanced lymphocyte transmigration across endothelial monolayers. Western blot (p38 phosphorylation), immunofluorescence (ZO-1, VE-cadherin, F-actin), RITC-dextran flux permeability assay, transendothelial lymphocyte migration assay, in vivo pial microvessel occlusion technique, fluorescein angiography in mouse retinae Brain, behavior, & immunity - health Medium 34755124
2016 Hypoxia-conditioned macrophages promote glioblastoma cell invasion via CCL4-CCR5 axis. Hypoxia upregulates CCR5 expression on GBM cells and elevates CCL4 secretion from macrophages via IRF-8. CCL4 from hypoxic macrophage supernatants enhanced GBM invasion and MMP-9 expression, and this effect was mediated through CCR5 signaling. GBM cell invasion assay, macrophage supernatant treatment, CCR5 expression analysis, CCL4 ELISA, IRF-8 involvement analysis Oncology reports Low 27748906
2018 CCL4 enhances preosteoclast cell migration and viability via CCR5. RANKL treatment rapidly downregulates CCR5 expression on preosteoclasts via MEK and JNK signaling, and this CCR5 downregulation promotes osteoclastogenesis. IFN-γ recovers CCR5 expression and antagonizes the pro-osteoclastogenic effect. CCL4 migration and viability assays in preosteoclast cells, CCR5 expression analysis upon RANKL treatment, MEK and JNK pharmacological inhibition, IFN-γ treatment, osteoclast differentiation assay Cell death & disease Medium 29717113
2019 CCL4 acts as a chemoattractant for eosinophils. IL-5-stimulated human eosinophils predominantly secrete CCL4. In a mouse model, administration of a CCL4-neutralizing antibody attenuated eosinophilic airway infiltration and airway hyperresponsiveness. In vitro eosinophil stimulation and CCL4 measurement, in vitro eosinophil chemotaxis assay, in vivo mouse model with CCL4-neutralizing antibody, airway hyperresponsiveness measurement Clinical and experimental allergy Medium 30854716
2007 CCL4 delivery to NOD mice via plasmid vector protects against type 1 diabetes by suppressing CD8+ T cell recruitment to islets (with decreased CCR5 expression on CD8+ T cells), inducing a Th2-like response in spleen and pancreas, and promoting regulatory T cell activity in draining pancreatic lymph nodes. Antibody neutralization of CCL4 abrogated protection transferred by T cells from IL-4-treated NOD mice. Plasmid-based in vivo CCL4 delivery, CCL4 antibody neutralization, T cell transfer protection assay, flow cytometry of T cell subsets and CCR5 expression, Th1/Th2 cytokine profiling Diabetes Medium 17327452
2013 EBV latent membrane protein 1 (LMP1) upregulates CCL4 (and CCL3) in EBV-infected B cells via Jun N-terminal protein kinase (JNK) activation. Autocrine CCL4 and CCL3 are required for lymphoblastoid cell line (LCL) survival and proliferation; shRNA knockdown or neutralizing antibodies to CCL4/CCL3 suppressed cell proliferation and caused apoptosis. Cytokine antibody arrays, EBV-infection/LMP1 expression model, JNK inhibitor treatment, shRNA knockdown, neutralizing antibodies to CCL4/CCL3, proliferation and apoptosis assays Journal of virology Medium 23760235
2021 CCL4 promotes osteosarcoma cell migration via CCR5, activating FAK, AKT, and HIF-1α signaling pathways, which downregulate miR-3927-3p, leading to upregulation of integrin αvβ3. Pharmacological inhibition of CCR5 with maraviroc prevented CCL4-induced integrin αvβ3 upregulation and cell migration. CCL4/CCR5 signaling pathway analysis, FAK/AKT/HIF-1α inhibitor treatment, miR-3927-3p expression analysis, integrin αvβ3 expression assay, CCR5 antagonist (maraviroc) treatment, cell migration assay International journal of molecular sciences Low 34884541
1999 CCL4 (MIP-1β) does not bind to or signal through CCR8 at physiologically relevant concentrations. CCL4 did not bind CCR8 on stably transfected cells or on human Th2 cells, did not induce CCR8-mediated chemotaxis, and did not desensitize I-309-dependent Ca2+ mobilization through CCR8. CCR8-transfected cell line binding assay, chemotaxis assay, Ca2+ mobilization and receptor desensitization assay, binding on in vitro differentiated human CD4+ Th2 cells European journal of immunology Medium 10540332
1993 Microinjection of CCL4 (MIP-1β) into the anterior hypothalamic preoptic area of rats evokes a monophasic fever (mean maximum ~2.1°C increase) and significantly attenuates food intake over 24 hours, demonstrating direct central nervous system actions on thermoregulation and feeding. Stereotaxic microinjection into rat anterior hypothalamus/preoptic area, body temperature telemetry, food and water intake monitoring Neurochemical research Low 8510794

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
1993 T-cell adhesion induced by proteoglycan-immobilized cytokine MIP-1 beta. Nature 848 7678446
1993 Preferential migration of activated CD4+ and CD8+ T cells in response to MIP-1 alpha and MIP-1 beta. Science (New York, N.Y.) 745 7682337
1993 Human macrophage inflammatory protein alpha (MIP-1 alpha) and MIP-1 beta chemokines attract distinct populations of lymphocytes. The Journal of experimental medicine 505 7684437
2004 Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice. Hepatology (Baltimore, Md.) 430 15565662
2001 B cells and professional APCs recruit regulatory T cells via CCL4. Nature immunology 397 11702067
1995 Actions of the chemotactic cytokines MCP-1, MCP-2, MCP-3, RANTES, MIP-1 alpha and MIP-1 beta on human monocytes. European journal of immunology 308 7531149
2006 The chemokines, CX3CL1, CCL14, and CCL4, promote human trophoblast migration at the feto-maternal interface. Biology of reproduction 173 16452465
2016 Mechanisms of CCl4-induced liver fibrosis with combined transcriptomic and proteomic analysis. The Journal of toxicological sciences 157 27452039
1995 Chemokine expression in rheumatoid arthritis (RA): evidence of RANTES and macrophage inflammatory protein (MIP)-1 beta production by synovial T cells. Clinical and experimental immunology 153 7545093
1998 Cytokine induction of MIP-1 alpha and MIP-1 beta in human fetal microglia. Journal of immunology (Baltimore, Md. : 1950) 140 9570566
2010 Polymerization of MIP-1 chemokine (CCL3 and CCL4) and clearance of MIP-1 by insulin-degrading enzyme. The EMBO journal 138 20959807
2012 CCl4-induced hepatotoxicity: protective effect of rutin on p53, CYP2E1 and the antioxidative status in rat. BMC complementary and alternative medicine 136 23043521
2020 CCL4 Signaling in the Tumor Microenvironment. Advances in experimental medicine and biology 131 32060843
2013 Infiltrating macrophages promote prostate tumorigenesis via modulating androgen receptor-mediated CCL4-STAT3 signaling. Cancer research 131 23878190
2003 Foxf1 +/- mice exhibit defective stellate cell activation and abnormal liver regeneration following CCl4 injury. Hepatology (Baltimore, Md.) 117 12500195
2015 Quercetin protects mouse liver against CCl₄-induced inflammation by the TLR2/4 and MAPK/NF-κB pathway. International immunopharmacology 116 26218279
2000 CC chemokine MIP-1 beta can function as a monomer and depends on Phe13 for receptor binding. Biochemistry 97 10727234
2010 FXR regulates liver repair after CCl4-induced toxic injury. Molecular endocrinology (Baltimore, Md.) 93 20211986
1991 Macrophage inflammatory protein (MIP)-1 beta abrogates the capacity of MIP-1 alpha to suppress myeloid progenitor cell growth. Journal of immunology (Baltimore, Md. : 1950) 90 1918979
2000 Expression of the beta-chemokines RANTES and MIP-1 beta by human brain microvessel endothelial cells in primary culture. Journal of neuropathology and experimental neurology 84 10888363
1982 Evidence for aldehydes bound to liver microsomal protein following CCl4 or BrCCl3 poisoning. Biochimica et biophysica acta 83 7093302
1997 Tissue injury and repair as parallel and opposing responses to CCl4 hepatotoxicity: a novel dose-response. Toxicology 81 9129172
2018 High levels of CCL2 or CCL4 in the tumor microenvironment predict unfavorable survival in lung adenocarcinoma. Thoracic cancer 79 29722145
2020 Alemtuzumab plus CHOP versus CHOP in elderly patients with peripheral T-cell lymphoma: the DSHNHL2006-1B/ACT-2 trial. Leukemia 77 32382083
2010 Prevention of CCl4-induced nephrotoxicity with Sonchus asper in rat. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 75 20550952
2016 Protective effect of wedelolactone against CCl4-induced acute liver injury in mice. International immunopharmacology 71 26921731
2012 Hepatoprotective effects of baicalein against CCl₄-induced acute liver injury in mice. World journal of gastroenterology 71 23236235
2007 Mathematical modelling of liver regeneration after intoxication with CCl(4). Chemico-biological interactions 70 17442287
1989 Protection of hepatotoxic and lethal effects of CCl4 by partial hepatectomy. Toxicologic pathology 67 2814225
2023 Mangiferin relieves CCl4-induced liver fibrosis in mice. Scientific reports 65 36914687
2015 MicroRNA-125b and chemokine CCL4 expression are associated with calcific aortic valve disease. Annals of medicine 63 26203686
2018 PSTPIP2 connects DNA methylation to macrophage polarization in CCL4-induced mouse model of hepatic fibrosis. Oncogene 62 29993036
2009 An arrestin-dependent multi-kinase signaling complex mediates MIP-1beta/CCL4 signaling and chemotaxis of primary human macrophages. Journal of leukocyte biology 62 19620252
2006 Induction of Gas6 protein in CCl4-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells. Hepatology (Baltimore, Md.) 61 16799993
2002 Activation of monocytic cells through Fc gamma receptors induces the expression of macrophage-inflammatory protein (MIP)-1 alpha, MIP-1 beta, and RANTES. Journal of immunology (Baltimore, Md. : 1950) 59 12218153
2007 Fucoidan partly prevents CCl4-induced liver fibrosis. European journal of pharmacology 56 18068155
1995 Inactivation and degradation of human cytochrome P4502E1 by CCl4 in a transfected HepG2 cell line. The Journal of pharmacology and experimental therapeutics 56 8531136
2016 Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis. Oncology reports 54 27748906
1988 Changes in albumin, alpha-fetoprotein and collagen gene transcription in CCl4-induced hepatic fibrosis. Hepatology (Baltimore, Md.) 52 2451632
2015 MicroRNA-125b modulates inflammatory chemokine CCL4 expression in immune cells and its reduction causes CCL4 increase with age. Aging cell 50 25620312
2020 CCL4 Inhibition in Atherosclerosis: Effects on Plaque Stability, Endothelial Cell Adhesiveness, and Macrophages Activation. International journal of molecular sciences 49 32911750
2014 CCl4 induced genotoxicity and DNA oxidative damages in rats: hepatoprotective effect of Sonchus arvensis. BMC complementary and alternative medicine 49 25412679
1980 Functional and biochemical correlates of chlordecone exposure and its enhancement of CCl4 hepatotoxicity. Toxicology 49 6154986
2002 Natural truncation of the chemokine MIP-1 beta /CCL4 affects receptor specificity but not anti-HIV-1 activity. The Journal of biological chemistry 47 12070155
2017 Macrophage-derived foam cells impair endothelial barrier function by inducing endothelial-mesenchymal transition via CCL-4. International journal of molecular medicine 46 28656247
1991 Colchicine antimitosis abolishes CCl4 autoprotection. Toxicologic pathology 46 1824173
2021 CCL4 induces inflammatory signalling and barrier disruption in the neurovascular endothelium. Brain, behavior, & immunity - health 45 34755124
2005 Expression of the beta chemokines CCL3, CCL4, CCL5 and their receptors in idiopathic inflammatory myopathies. Neuropathology and applied neurobiology 45 15634233
1999 Transplanted hepatocytes proliferate differently after CCl4 treatment and hepatocyte growth factor infusion. The American journal of physiology 45 10070039
2014 Reversing effects of lignans on CCl4-induced hepatic CYP450 down regulation by attenuating oxidative stress. Journal of ethnopharmacology 44 24910408
2006 Therapeutic effect of interleukin-10 on CCl4-induced hepatic fibrosis in rats. World journal of gastroenterology 42 16552806
2013 Attenuation of CCl4-induced hepatic fibrosis in mice by vaccinating against TGF-β1. PloS one 40 24349218
1983 Acute hepatotoxicity and lethality of CCl4 in chlordecone-pretreated rats. Experimental and molecular pathology 40 6192011
2018 CCL4 enhances preosteoclast migration and its receptor CCR5 downregulation by RANKL promotes osteoclastogenesis. Cell death & disease 39 29717113
2005 Multiple products derived from two CCL4 loci: high incidence of a new polymorphism in HIV+ patients. Journal of immunology (Baltimore, Md. : 1950) 38 15843566
2001 MIP-1 alpha and MIP-1 beta induction by dengue virus. Journal of medical virology 38 11536240
2016 Resveratrol can prevent CCl₄-induced liver injury by inhibiting Notch signaling pathway. Histology and histopathology 37 26742567
2014 Inhibitory effect of gallic acid on CCl4-mediated liver fibrosis in mice. Cell biochemistry and biophysics 37 24096707
2010 Morphological and molecular pathology of CCL4-induced hepatic fibrosis in connexin43-deficient mice. Microscopy research and technique 36 20830702
1993 Fever and feeding: differential actions of macrophage inflammatory protein-1 (MIP-1), MIP-1 alpha and MIP-1 beta on rat hypothalamus. Neurochemical research 35 8510794
2022 Sini San ameliorates CCl4-induced liver fibrosis in mice by inhibiting AKT-mediated hepatocyte apoptosis. Journal of ethnopharmacology 34 36460296
2019 Critical role of CCL4 in eosinophil recruitment into the airway. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 34 30854716
2006 Conditional dominant mutations in the Caenorhabditis elegans gene act-2 identify cytoplasmic and muscle roles for a redundant actin isoform. Molecular biology of the cell 34 16407404
2007 CCL4 protects from type 1 diabetes by altering islet beta-cell-targeted inflammatory responses. Diabetes 33 17327452
2006 Mantle cell lymphomas acquire increased expression of CCL4, CCL5 and 4-1BB-L implicated in cell survival. International journal of cancer 33 16287062
2006 Cytokine and chemokine transcription profile during Mycoplasma pulmonis infection in susceptible and resistant strains of mice: macrophage inflammatory protein 1beta (CCL4) and monocyte chemoattractant protein 2 (CCL8) and accumulation of CCR5+ Th cells. Infection and immunity 33 16988274
1989 Protective role of fructose 1,6-bisphosphate during CCl4 hepatotoxicity in rats. The Biochemical journal 33 2590162
2016 Hepatocyte ERBB3 and EGFR are required for maximal CCl4-induced liver fibrosis. American journal of physiology. Gastrointestinal and liver physiology 32 27586651
2013 Oroxylin A accelerates liver regeneration in CCl₄-induced acute liver injury mice. PloS one 32 23951204
2002 Taurocholate feeding prevents CCl4-induced damage of large cholangiocytes through PI3-kinase-dependent mechanism. American journal of physiology. Gastrointestinal and liver physiology 32 12388182
2023 The FDA modernisation act 2.0: Bringing non-animal technologies to the regulatory table. Drug discovery today 31 36690176
2021 p53-mediated redox control promotes liver regeneration and maintains liver function in response to CCl4. Cell death and differentiation 31 34628485
2011 CCL4L polymorphisms and CCL4/CCL4L serum levels are associated with psoriasis severity. The Journal of investigative dermatology 31 21614014
2009 Expression of angiotensin-converting enzyme 2 in CCL4-induced rat liver fibrosis. International journal of molecular medicine 31 19424597
2004 Ginkgo biloba extract reverses CCl4-induced liver fibrosis in rats. World journal of gastroenterology 31 15052689
2021 CCL4 Stimulates Cell Migration in Human Osteosarcoma via the mir-3927-3p/Integrin αvβ3 Axis. International journal of molecular sciences 30 34884541
2016 Proficiencies of Artemisia scoparia against CCl4 induced DNA damages and renal toxicity in rat. BMC complementary and alternative medicine 30 27233360
2015 Blockade of CCN4 attenuates CCl4-induced liver fibrosis. Archives of medical science : AMS 29 26170860
2011 Status epilepticus evokes prolonged increase in the expression of CCL3 and CCL4 mRNA and protein in the rat brain. Acta neurobiologiae experimentalis 29 21731074
1999 The assignment of chemokine-chemokine receptor pairs: TARC and MIP-1 beta are not ligands for human CC-chemokine receptor 8. European journal of immunology 29 10540332
2016 Deferoxamine alleviates liver fibrosis induced by CCl4 in rats. Clinical and experimental pharmacology & physiology 28 27168353
2016 MicroRNA Expression Profiling in CCl₄-Induced Liver Fibrosis of Mus musculus. International journal of molecular sciences 28 27322257
2013 Autocrine CCL3 and CCL4 induced by the oncoprotein LMP1 promote Epstein-Barr virus-triggered B cell proliferation. Journal of virology 28 23760235
2013 Berberine and S allyl cysteine mediated amelioration of DEN+CCl4 induced hepatocarcinoma. Biochimica et biophysica acta 28 23999088
2017 Resveratrol alleviates FFA and CCl4 induced apoptosis in HepG2 cells via restoring endoplasmic reticulum stress. Oncotarget 27 28415630
2017 Vatalanib, a tyrosine kinase inhibitor, decreases hepatic fibrosis and sinusoidal capillarization in CCl4-induced fibrotic mice. Molecular medicine reports 27 28447731
2004 Amino-terminal processing of MIP-1beta/CCL4 by CD26/dipeptidyl-peptidase IV. Journal of cellular biochemistry 27 15095403
2002 Characterization of the role of the N-loop of MIP-1 beta in CCR5 binding. Biochemistry 27 12427015
1990 Mitochondrial structure and function in CCl4-induced cirrhosis in the rat. Hepatology (Baltimore, Md.) 27 2205557
2012 Isorhamnetin-3-O-galactoside Protects against CCl4-Induced Hepatic Injury in Mice. Biomolecules & therapeutics 26 24009828
2016 mTOR Overactivation in Mesenchymal cells Aggravates CCl4- Induced liver Fibrosis. Scientific reports 25 27819329
2015 Comparison of TGF-β, PDGF, and CTGF in hepatic fibrosis models using DMN, CCl4, and TAA. Drug and chemical toxicology 25 26045230
2011 Neutralization of chemokine CXCL14 (BRAK) expression reduces CCl4 induced liver injury and steatosis in mice. European journal of pharmacology 25 21978833
2003 Changes in activin and activin receptor subunit expression in rat liver during the development of CCl4-induced cirrhosis. Molecular and cellular endocrinology 25 12706302
2015 Anti-fibrotic effect of plumbagin on CCl₄-lesioned rats. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 23 25824458
2001 Increased expression of MIP-1 alpha and MIP-1 beta mRNAs in the brain correlates spatially and temporally with the spongiform neurodegeneration induced by a murine oncornavirus. Journal of virology 23 11222690
1990 Identification of cell surface receptors for the Act-2 cytokine. The Journal of experimental medicine 23 2193098
2015 Structures of human CCL18, CCL3, and CCL4 reveal molecular determinants for quaternary structures and sensitivity to insulin-degrading enzyme. Journal of molecular biology 22 25636406
2018 Protective aptitude of Periploca hydaspidis Falc against CCl4 induced hepatotoxicity in experimental rats. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 21 30021348

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