Affinage

CCL2

C-C motif chemokine 2 · UniProt P13500

Round 2 corrected
Length
99 aa
Mass
11.0 kDa
Annotated
2026-04-28
130 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCL2 (MCP-1) is a secreted CC chemokine that functions as a principal monocyte/macrophage chemoattractant and activator, orchestrating innate immune cell recruitment in inflammation, tissue repair, metabolic disease, neurodegeneration, and tumor progression. The mature 76-residue protein signals primarily through the Gαi-coupled receptor CCR2 to trigger β2-integrin-dependent firm adhesion to endothelium, iPLA2β-regulated actin polarization and directional migration, and downstream PI3K/Akt, Src/MAPK, and NF-κB cascades; beyond chemotaxis, CCL2–CCR2 signaling promotes M2 macrophage polarization via caspase-8 inhibition and autophagy, drives myofibroblast transdifferentiation, modulates osteoclastogenesis, and enhances excitatory synaptic transmission in spinal neurons (PMID:2161898, PMID:12388329, PMID:18208975, PMID:19833726, PMID:19339605, PMID:21678414). Transcription is controlled by an NF-κB distal enhancer and a proximal Sp1 site, with additional regulation by IκBζ-dependent H3K4 trimethylation, ATF4, BMI1-mediated H2AK119Ub repression, and Notch/RBPJκ in hepatocytes (PMID:8051410, PMID:23547114, PMID:26573462, PMID:36752206). CCL2 activity is terminated post-translationally by MMP-1/MMP-3 cleavage between residues 4–5, generating a CCR2 antagonist, or by reactive nitrogen species–mediated nitration that abolishes leukocyte recruitment (PMID:12149192, PMID:21930770).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1989 High

    Molecular cloning of CCL2 from two independent laboratories established its identity as a 99-residue precursor (23-aa signal peptide + 76-aa mature protein) belonging to the CC chemokine family, providing the sequence foundation for all subsequent structure–function work.

    Evidence cDNA cloning and sequencing from glioma cell line and stimulated PBMCs

    PMID:2465924 PMID:2923622

    Open questions at the time
    • Three-dimensional structure not yet determined at this stage
    • Receptor identity unknown
    • Post-translational modifications uncharacterized
  2. 1990 High

    Purified CCL2 was shown to bind a specific receptor on monocytes distinct from IL-8 receptors and to activate superoxide release, lysosomal enzyme secretion, tumoricidal activity, and in vivo monocyte infiltration, establishing it as both a chemoattractant and a monocyte activator.

    Evidence 125I-labeled MCAF competitive binding, functional assays on purified human monocytes, in vivo rat ear injection

    PMID:2161898

    Open questions at the time
    • Receptor molecular identity not yet cloned
    • Intracellular signaling cascade undefined
    • Redundancy with other CC chemokines not addressed
  3. 1994 High

    Promoter dissection resolved how CCL2 transcription is controlled, identifying a distal NF-κB site required for cytokine-induced expression and a proximal Sp1 GC-box for basal activity, explaining how diverse inflammatory stimuli converge on CCL2 induction.

    Evidence 5′-flanking sequence analysis, promoter-reporter mutagenesis, Sp1 overexpression

    PMID:8051410

    Open questions at the time
    • Chromatin-level regulation and epigenetic marks not addressed
    • Cell-type-specific promoter usage not explored
    • Role of enhancer elements beyond the distal NF-κB site unknown
  4. 2001 High

    CCL2 knockout mice revealed an unexpected role beyond monocyte recruitment: impaired wound re-epithelialization, angiogenesis, and collagen synthesis without altered macrophage numbers, demonstrating that CCL2 regulates macrophage effector function in tissue repair.

    Evidence MCP-1 knockout mice, wound healing assay, histology, hydroxyproline and capillary density quantification

    PMID:11485904

    Open questions at the time
    • Downstream effector signals in wound macrophages not identified
    • Whether CCR2-independent receptors contribute not tested
    • Compensatory chemokine upregulation not assessed
  5. 2002 High

    Two advances defined how CCL2 signaling is executed and terminated: endothelial CCL2 was shown to trigger β2-integrin activation and firm monocyte adhesion under flow via CCR2, while MMP-1/MMP-3 cleavage between residues 4–5 was found to generate a truncated CCR2 antagonist that blocks chemotaxis and reduces inflammation in vivo.

    Evidence Flow chamber with anti-integrin/anti-CCR2 blocking antibodies; recombinant MMP cleavage with receptor binding and in vivo carrageenan model

    PMID:12149192 PMID:12388329

    Open questions at the time
    • Structural basis of MMP cleavage site selectivity not resolved
    • Kinetics of MMP-mediated inactivation in tissue contexts unknown
    • Whether other proteases generate similar antagonistic fragments not tested
  6. 2006 High

    Gain-of-function (transgenic), loss-of-function (knockout), and dominant-negative approaches in mice causally linked CCL2 to adipose tissue macrophage infiltration, insulin resistance, and hepatic steatosis, establishing CCL2 as a key mediator of obesity-associated metabolic inflammation.

    Evidence aP2-MCP-1 transgenic mice, MCP-1 knockout mice, dominant-negative mutant gene delivery, metabolic phenotyping

    PMID:16691291

    Open questions at the time
    • Relative contributions of adipocyte- vs. macrophage-derived CCL2 not separated
    • Direct hepatic signaling targets of CCL2 in steatosis undefined
    • Human genetic evidence for CCL2 in metabolic syndrome not provided
  7. 2008 High

    iPLA2β and cPLA2α were identified as spatially segregated effectors downstream of CCL2-induced chemotaxis: iPLA2β localizes to the pseudopod and controls directionality and actin polymerization, while cPLA2α at the ER controls migration speed, explaining how a single chemokine generates multi-component migratory responses.

    Evidence Antisense knockdown, subcellular localization imaging, actin polymerization assay, adoptive transfer migration in vivo

    PMID:18208975

    Open questions at the time
    • Lipid products mediating each PLA2 branch not identified
    • How CCR2 differentially activates iPLA2β vs. cPLA2α unknown
    • Whether this mechanism applies to other CC chemokine receptors untested
  8. 2009 High

    CCL2 was placed in neural circuitry: TNF-α/JNK induces astrocytic CCL2, which activates ERK in spinal dorsal horn neurons, enhances excitatory postsynaptic currents, and potentiates NMDA/AMPA responses, defining a glial-to-neuronal CCL2 signaling axis in neuropathic pain central sensitization.

    Evidence JNK inhibitors, spinal nerve ligation model, intrathecal MCP-1 neutralizing antibody, patch-clamp electrophysiology

    PMID:19339605

    Open questions at the time
    • Direct neuronal receptor mediating synaptic potentiation not confirmed as CCR2 vs. alternative
    • Whether astrocytic CCL2 acts presynaptically or postsynaptically not resolved
    • Contribution relative to other pain chemokines not quantified
  9. 2011 High

    CCL2 was shown to be subject to reactive nitrogen species–mediated nitration in the tumor microenvironment, which abolishes T-cell recruitment into tumor cores; pharmacological inhibition of nitration restored CTL infiltration, identifying post-translational nitration as a tumor immune evasion mechanism.

    Evidence RNS detection, chemokine nitration biochemistry, T-cell trafficking assays, pharmacological inhibition in mouse and human tumors

    PMID:21930770

    Open questions at the time
    • Specific tyrosine residue(s) nitrated not mapped
    • Whether nitrated CCL2 acquires gain-of-function activities unknown
    • Generalizability to other chemokines in the tumor microenvironment not tested
  10. 2011 High

    CCL2 was causally linked to breast cancer metastasis: tumor/stromal CCL2 recruits CCR2+Ly-6C+ inflammatory monocytes to pulmonary metastatic sites, and these monocytes promote tumor cell extravasation through VEGF production, defining a CCL2→CCR2→VEGF→extravasation metastatic axis.

    Evidence CCL2-knockout mice, antibody blockade, bone marrow chimeras, monocyte depletion, in vivo metastasis model

    PMID:21654748

    Open questions at the time
    • Whether tumor cells co-opt additional CCL2-independent monocyte recruitment pathways not assessed
    • Precise mechanism by which monocyte-derived VEGF promotes extravasation not defined
    • Clinical relevance of CCL2 blockade withdrawal (rebound effect) not addressed
  11. 2013 High

    IκBζ was identified as a direct transcriptional coactivator of Ccl2 by ChIP, linking NF-κB to epigenetic activation: IκBζ binding enables H3K4 trimethylation at the Ccl2 promoter, and IκBζ-deficient macrophages show impaired CCL2 secretion and monocyte recruitment in vivo.

    Evidence IκBζ-knockout macrophages, ChIP for IκBζ and H3K4me3, peritonitis model, ELISA

    PMID:23547114

    Open questions at the time
    • Methyltransferase recruited by IκBζ not identified
    • Whether IκBζ cooperates with Sp1 at the proximal promoter untested
    • Kinetics of epigenetic mark deposition relative to transcription initiation unknown
  12. 2016 High

    A senescence-associated feed-forward loop was defined: secreted CCL2 activates CCR2→ROS→p38→p53/p21 in mesenchymal stromal cells, and activated p53 further increases CCL2 transcription; BMI1 was identified as an epigenetic repressor that silences CCL2 via H2AK119Ub, with BMI1 decline during senescence derepressing CCL2.

    Evidence CCR2 knockdown, p38/MAPK/p53 inhibitors, ChIP for BMI1 and H2AK119Ub, ROS measurement

    PMID:26573462

    Open questions at the time
    • Whether BMI1 loss is a cause or consequence of senescence initiation not fully resolved
    • Quantitative contribution of autocrine vs. paracrine CCL2 loop not measured
    • Whether this loop operates in epithelial senescence unknown
  13. 2023 High

    Hepatocyte-specific CCL2 was found to be transcriptionally driven by Notch signaling through a conserved RBPJκ binding site in the Ccl2 promoter; hepatocyte-specific Ccl2 knockout reduced monocyte-derived macrophage infiltration and liver fibrosis in NASH, directly linking cell-type-specific CCL2 production to metabolic liver disease.

    Evidence Hepatocyte-specific Ccl2 knockout, Notch gain-of-function mice, RBPJκ promoter analysis, CCR2 inhibitor rescue, liver fibrosis quantification

    PMID:36752206

    Open questions at the time
    • Whether Notch-driven CCL2 operates in other parenchymal cell types unknown
    • Interaction between RBPJκ and NF-κB/Sp1 on the CCL2 promoter not characterized
    • Therapeutic window for CCR2 inhibition in human NASH not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite extensive characterization, the full structural basis of CCL2–CCR2 activation (including the role of CCL2 oligomerization on GAGs in vivo), the identity of the non-CCR2 receptor mediating fibroblast transdifferentiation, and the quantitative contribution of individual cell-type-specific CCL2 sources across disease contexts remain unresolved.
  • No high-resolution structure of the CCL2–CCR2 signaling complex in a lipid bilayer
  • Non-CCR2 receptor on fibroblasts not molecularly identified
  • Systems-level quantification of tissue-specific CCL2 sources in vivo lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005576 extracellular region 7
Pathway
R-HSA-168256 Immune System 9 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 5 R-HSA-74160 Gene expression (Transcription) 4
Partners
ATF4BMI1CCR2MMP1MMP3NFKB1NFKBIZSP1

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 CCL2/MCP-1 was cloned and sequenced from a glioma cell line cDNA library; the precursor protein consists of a 23-residue signal peptide and a 76-residue mature protein, establishing it as a member of the inducible cytokine family with sequence similarity to mouse JE, RANTES, MIP, and TCA-3. cDNA cloning, nucleotide sequencing, amino acid sequence analysis Biochemical and biophysical research communications / FEBS letters High 2465924 2923622
1989 CCL2/MCP-1 mRNA is induced in human peripheral blood mononuclear leukocytes by PHA, LPS, and IL-1, but not by IL-2, TNF, or IFN-γ, defining the stimulus-specific transcriptional regulation of the gene. Northern blot analysis, mRNA induction assays FEBS letters High 2465924
1990 Purified CCL2/MCAF specifically binds to receptors on human PBMC that are distinct from those used by IL-8, stimulates superoxide anion release and N-acetyl-β-D-glucosaminidase secretion in human monocytes, augments monocyte cytostatic activity against tumor cells, and induces in vivo local monocyte infiltration in rat ears, establishing CCL2 as both a monocyte chemoattractant and activator. Protein purification, competitive receptor-binding assays with 125I-labeled MCAF, in vitro functional assays, in vivo subcutaneous injection The Journal of experimental medicine High 2161898
1994 Transcription of the human CCL2 gene is controlled by two critical cis-elements: a remote NF-κB binding site (at bp −2612 to −2603) required for IL-1β-, TNF-α-, and PMA-induced enhancer activity, and a proximal GC box (bp −64 to −59) bound by Sp1 that maintains basal transcriptional activity. 5′-flanking genomic DNA sequencing, promoter-reporter assays, site-directed mutagenesis, Sp1 overexpression Journal of immunology High 8051410
2001 CCL2/MCP-1 knockout mice show significantly delayed wound re-epithelialization, reduced angiogenesis, and impaired collagen synthesis compared to wild-type, without a change in macrophage numbers in wounds, indicating CCL2 regulates the effector state of macrophages and other wound-repair cells rather than simply mediating monocyte recruitment into wounds. MCP-1 knockout mouse model, wound healing assay, histology, hydroxyproline quantification, capillary density measurement The American journal of pathology High 11485904
2002 Matrix metalloproteinases MMP-1 and MMP-3 cleave CCL2 between residues 4 and 5; the resulting truncated CCL2 product binds CCR2 but lacks chemoattractant activity and acts as a CCR2 antagonist, reducing inflammatory edema in vivo by >66%, revealing a proteolytic mechanism by which MMPs terminate CCL2-driven chemotaxis. Recombinant MMP cleavage assays, receptor-binding assays, transwell migration assays, in vivo carrageenan inflammation model Blood High 12149192
2002 Endothelial-derived CCL2 signals through monocyte CCR2 to promote firm monocyte adhesion to inflamed endothelium under physiological flow via the β2-integrin (but not β1-integrin) pathway; MCP-1 stimulation causes rapid β2-integrin neoepitope 24 expression on monocytes, establishing a mechanistic link between endothelial CCL2 and integrin-mediated monocyte adhesion. Flow chamber assay, anti-MCP-1 neutralizing antibody, antisense oligomers, CCR2 blockade, anti-integrin antibodies, reporter mAb24 binding American journal of physiology. Heart and circulatory physiology High 12388329
2005 CCL2 secreted by bile duct epithelia acts in a paracrine manner on portal fibroblasts to induce their proliferation, α-smooth muscle actin redistribution (myofibroblastic transdifferentiation), loss of NTPDase2, and upregulation of α1-procollagen; these effects are mediated by a receptor on portal fibroblasts distinct from CCR2. MCP-1 blocking antibody, paracrine co-culture assays, proliferation assays, immunofluorescence for α-SMA, NTPDase2 assay, procollagen measurement American journal of physiology. Gastrointestinal and liver physiology Medium 16282363
2006 MCP-1 transgenic overexpression in adipose tissue causes macrophage infiltration, insulin resistance, and hepatic steatosis, while MCP-1 knockout reduces these phenotypes in diet-induced obese mice, and acute expression of a dominant-negative MCP-1 mutant ameliorates insulin resistance, establishing a causal role of CCL2 in obesity-induced metabolic inflammation. Transgenic mouse overexpression (aP2-MCP-1), MCP-1 homozygous knockout mice, dominant-negative mutant gene delivery, metabolic phenotyping The Journal of clinical investigation High 16691291
2007 EBV virions induce MCP-1 secretion from human monocytes through TLR2 recognition, activating NF-κB; siRNA-mediated TLR2 knockdown significantly reduces CCL2 release, identifying TLR2 as the pattern recognition receptor upstream of CCL2 induction during EBV infection. TLR2-expressing HEK293 transfection, NF-κB-luciferase reporter assay, blocking anti-TLR2 antibodies, siRNA knockdown, ELISA Journal of virology Medium 17522215
2008 12(S)-HETE (a product of 12/15-lipoxygenase) increases CCL2 mRNA and protein expression in macrophages via sequential activation of PKC, p38 MAPK, and NADPH oxidase; 12/15-LO knockout mice have reduced macrophage MCP-1 expression, and transgenic overexpression of 12/15-LO increases it, defining a 12/15-LO→PKC/p38/NADPH oxidase→CCL2 regulatory axis. 12(S)-HETE treatment, PKC/p38/NADPH oxidase pharmacological inhibitors, 12/15-LO transgenic and knockout mouse peritoneal macrophages, stable 12/15-LO overexpressing cell line American journal of physiology. Heart and circulatory physiology High 18296557
2008 Upon MCP-1 stimulation, iPLA2β translocates to the membrane-enriched pseudopod while cPLA2α is recruited to the endoplasmic reticulum; iPLA2β regulates monocyte directionality and actin polymerization in addition to speed, whereas cPLA2α affects speed alone; antisense knockdown of either enzyme impairs monocyte migration to the peritoneum in vivo. Antisense oligodeoxynucleotides, subcellular localization imaging, transwell chemotaxis assays, actin polymerization assay, adoptive transfer in vivo migration assay The Journal of experimental medicine High 18208975
2009 TNF-α activates JNK in spinal astrocytes via TNF receptor-1, leading to CCL2/MCP-1 induction; JNK inhibitors block this upregulation dose-dependently. Spinal MCP-1 subsequently activates ERK in dorsal horn neurons, enhances spontaneous EPSCs, and potentiates NMDA- and AMPA-induced currents, contributing to central sensitization and neuropathic pain. JNK inhibitors (SP600125, D-JNKI-1), cytokine array, spinal nerve ligation model, MCP-1 neutralizing antibody intrathecal injection, patch-clamp recordings in spinal cord slices The Journal of neuroscience High 19339605
2009 Noradrenaline increases CCL2 expression in astrocytes via β2-adrenergic receptor–cAMP signaling activating the MCP-1 promoter; astrocyte-released MCP-1 reduces NMDA-dependent glutamate release and glutamate-mediated Ca2+ entry in neurons, protecting them from OGD-induced damage; neutralizing antibody to MCP-1 blocks the neuroprotective effect of conditioned medium from NA-treated astrocytes. β-adrenergic agonists/antagonists, cAMP analog, MCP-1 promoter–luciferase assay, MCP-1 neutralizing antibody, glutamate release assay, Ca2+ imaging, LDH assay, OGD model, transwell co-culture The Journal of neuroscience High 19129402
2010 Cocaine induces CCL2 expression in microglia through translocation of the sigma receptor to lipid raft microdomains, followed by sequential activation of Src, MAPKs, PI3K/Akt, and NF-κB; conditioned medium from cocaine-exposed microglia increases monocyte transmigration via CCR2, and this effect is absent in CCR2 knockout mice or with sigma receptor antagonist pretreatment. Sigma receptor antagonist, lipid raft fractionation, kinase inhibitors, CCR2 knockout mice, monocyte transmigration assay, in vivo cocaine exposure Blood High 20354174
2010 Thiamine deficiency selectively induces neuronal CCL2 expression prior to microglia activation; MCP-1 from thiamine-deficient neurons activates microglia to produce cytotoxic cytokines; MCP-1 neutralizing antibody inhibits microglia activation and neuronal death; CCL2 knockout mice are resistant to thiamine deficiency-induced neurodegeneration in the thalamus. Thiamine deficiency model, neuron/microglia co-culture, MCP-1 neutralizing antibody, CCL2 knockout mice, antioxidant treatment Brain pathology High 21029241
2011 CCL2 produced by tumor and stroma recruits Gr1+ inflammatory monocytes expressing CCR2 to pulmonary metastases; these inflammatory monocytes promote tumor cell extravasation via monocyte-derived VEGF; inhibition of CCL2-CCR2 signaling blocks monocyte recruitment and inhibits metastasis in vivo, defining a CCL2→CCR2→VEGF→extravasation mechanistic axis in breast cancer metastasis. CCL2-knockout mice, CCL2 antibody blockade, bone marrow chimeras, monocyte depletion, VEGF measurement, in vivo metastasis model Nature High 21654748
2011 Reactive nitrogen species within the tumor microenvironment nitrate CCL2, and this nitrated form fails to recruit T cells into the tumor core, trapping them in the surrounding stroma; drugs that inhibit CCL2 nitration restore CTL invasion, revealing RNS-mediated post-translational modification of CCL2 as a tumor immune evasion mechanism. RNS detection in tumor microenvironment, chemokine nitration biochemistry, T cell trafficking assays, pharmacological inhibition of CCL2 modification in mouse and human tumors The Journal of experimental medicine High 21930770
2012 CCL2 deficiency in ApcMin/+ mice reduces polyp number (especially large polyps) and decreases F4/80+ macrophages in polyp and intestinal tissue, shifts cytokine balance (reduces IL-1β, IL-6, increases SOCS1), increases cytotoxic T lymphocytes and decreases regulatory T cells, establishing CCL2 as a mediator of tumor-associated macrophage recruitment and immune regulation in intestinal tumorigenesis. MCP-1 knockout in ApcMin/+ genetic background, histology, immunohistochemistry, cytokine mRNA quantification American journal of physiology. Gastrointestinal and liver physiology Medium 23019193
2012 MCP-1 deficiency in mice leads to elevated bone mass due to reduced osteoclast number and activity; MCP-1-null osteoclast precursors show reduced c-Fms and RANK receptor levels, impaired actin ring formation, and reduced activation of ERK, Akt, Rac1, and Rho upon M-CSF stimulation, placing CCL2 upstream of M-CSF signaling and cytoskeletal organization in osteoclastogenesis. MCP-1 knockout mice, bone densitometry, serum CTX-1 and TRACP 5b, in vitro osteoclastogenesis, actin ring staining, Western blot for signaling molecules Journal of cellular physiology Medium 21678414
2013 IκBζ, an atypical IκB family member and NF-κB transcriptional coactivator, directly binds the proximal promoter of the Ccl2 gene (shown by ChIP) and is required for LPS- and peptidoglycan-induced CCL2 secretion in macrophages; IκBζ-deficient mice show impaired CCL2 secretion and monocyte infiltration in peritonitis; IκBζ binding enables transcription-enhancing H3K4 trimethylation at the Ccl2 promoter. IκBζ-knockout macrophages, chromatin immunoprecipitation (ChIP), histone methylation assay, peritonitis model, ELISA Journal of immunology High 23547114
2013 OxLDL binds CCL2 through oxidized phospholipids, and basic residues Arg-18 and Lys-19 in CCL2 are required for this interaction (shown by Arg18Ala/Lys19Ala mutant that fails to bind OxLDL); lipoprotein(a) in human plasma also binds CCL2 via oxidized phospholipids, and Lp(a)-associated endogenous MCP-1 retains monocyte-recruiting activity. OxLDL binding assay, site-directed mutagenesis (R18A/K19A), monoclonal antibody E06 blocking, human plasma Lp(a) capture, monocyte migration assay Journal of lipid research High 23667177
2014 CCL2 produced by tumor-derived macrophages/microglia recruits both CCR4+ regulatory T cells and CCR2+Ly-6C+ monocytic MDSCs into gliomas; glioma-derived CCL20 and osteoprotegerin induce CCL2 production from macrophages/microglia; in mixed bone marrow chimera assays, CCR4-deficient Tregs and CCR2-deficient monocytic MDSCs fail to accumulate in gliomas. CCL2-deficient mice, mixed bone marrow chimeras, CCR4/CCR2 knockout cells, small-molecule CCR4 antagonist, survival analysis Cancer research High 27530322
2014 CCL2 promotes macrophage M2 polarization: CCL2 enhances LPS-induced IL-10 production, while CCL2 blockade increases M1 markers and reduces M2 markers in human macrophages; Ccr2-deficient murine macrophages display M1-skewed polarization with higher TNF-α and IL-6 in response to LPS; activin A controls differential CCL2/CCR2 expression, inhibiting CCL2 acquisition by M-CSF-polarized macrophages. CCL2 blocking antibody, Ccr2-knockout bone marrow-derived macrophages, gene expression profiling, cytokine ELISA, activin A treatment Journal of immunology High 24639350
2015 ATF4, an ER stress-inducible transcription factor, is a key regulator of CCL2 production in microvascular endothelial cells; ATF4 overexpression increases CCL2 secretion and promotes monocyte adhesion, while ATF4-deficient endothelial cells and ATF4 heterozygous knockout retinas show markedly attenuated LPS-induced CCL2; ATF4 acts upstream of NF-κB, p38, and JNK phosphorylation to drive CCL2 expression. ATF4 knockout mice, adenoviral ATF4 overexpression/dominant-negative, LPS stimulation, pharmacological inhibition of NF-κB/p38/JNK, monocyte adhesion assay, intravitreal injection Journal of inflammation Medium 25914608
2016 During mesenchymal stromal cell senescence, MCP-1 is secreted as a dominant SASP component and reinforces senescence via CCR2-activated ROS-p38-MAPK-p53/p21 cascade in autocrine/paracrine fashion; activated p53 further increases MCP-1 secretion, forming a feed-forward loop; BMI1 epigenetically represses CCL2 expression by binding its regulatory elements and maintaining H2AK119Ub; BMI1 decline during senescence leads to loss of this mark and CCL2 derepression. CCR2 knockdown, p38/MAPK/p53 inhibitors, ChIP for BMI1 and H2AK119Ub, ROS measurement, SASP profiling by ELISA Antioxidants & redox signaling High 26573462
2019 CCL2/CCR2 signaling shapes macrophage behavior beyond chemotaxis, including promoting survival of CD11b+ monocytes via upregulation of cFLIPL, Bcl-2, and Bcl-XL and inhibition of caspase-8 cleavage; CCL2 induces autophagy hyperactivation and M2-type (CD206+) macrophage polarization; blockade of autophagic degradation reverses CCL2-induced M2 polarization. CCL2 stimulation of primary human CD11b+ cells, Western blot for apoptotic proteins, caspase-8 activity assays, flow cytometry for CD206, autophagy inhibitor treatment The Journal of biological chemistry Medium 19833726
2023 Hepatocyte-specific CCL2 expression is driven by Notch signaling through an evolutionarily conserved RBPjκ binding site in the Ccl2 promoter; hepatocyte-specific Ccl2 knockout reduces liver monocyte-derived macrophage infiltration and fibrosis in NASH, while forced hepatocyte MCP-1 expression produces the opposite phenotype; the effect is rescued by CCR2 inhibitor treatment. Hepatocyte-specific Ccl2 knockout mice, Notch gain-of-function mice, Ccl2 promoter analysis for RBPjκ binding site, CCR2 inhibitor treatment, liver histology and fibrosis quantification JCI insight High 36752206

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
2009 Monocyte chemoattractant protein-1 (MCP-1): an overview. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 3053 19441883
2011 CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 2355 21654748
2006 MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. The Journal of clinical investigation 2100 16691291
2010 Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature genetics 2036 21102463
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
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 MCP-1: Function, regulation, and involvement in disease. International immunopharmacology 676 34233864
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1989 Human monocyte chemoattractant protein-1 (MCP-1). Full-length cDNA cloning, expression in mitogen-stimulated blood mononuclear leukocytes, and sequence similarity to mouse competence gene JE. FEBS letters 593 2465924
1990 Human monocyte chemoattractant protein-1 (MCP-1). Immunology today 580 2186747
2011 Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. The Journal of experimental medicine 523 21930770
2016 CCL2 Produced by the Glioma Microenvironment Is Essential for the Recruitment of Regulatory T Cells and Myeloid-Derived Suppressor Cells. Cancer research 522 27530322
2019 More Than Just Attractive: How CCL2 Influences Myeloid Cell Behavior Beyond Chemotaxis. Frontiers in immunology 518 31921102
2009 JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. The Journal of neuroscience : the official journal of the Society for Neuroscience 490 19339605
1998 Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia. Proceedings of the National Academy of Sciences of the United States of America 483 9501225
2008 The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer letters 481 18439751
1994 NF-kappa B and Sp1 regulate transcription of the human monocyte chemoattractant protein-1 gene. Journal of immunology (Baltimore, Md. : 1950) 471 8051410
2009 CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization. The Journal of biological chemistry 463 19833726
2002 Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood 454 12149192
1996 Cloning, expression, and characterization of the human eosinophil eotaxin receptor. The Journal of experimental medicine 441 8642344
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2008 Peripheral cytokines profile in Parkinson's disease. Brain, behavior, and immunity 425 18678243
2007 Increased MCP-1 and microglia in various regions of the human alcoholic brain. Experimental neurology 424 18190912
2016 Targeting the CCL2-CCR2 signaling axis in cancer metastasis. Oncotarget 413 26885690
2000 Human galectin-3 is a novel chemoattractant for monocytes and macrophages. Journal of immunology (Baltimore, Md. : 1950) 409 10925302
2014 CCL2 shapes macrophage polarization by GM-CSF and M-CSF: identification of CCL2/CCR2-dependent gene expression profile. Journal of immunology (Baltimore, Md. : 1950) 408 24639350
2009 Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 370 19904283
2020 CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis. Molecular cancer 357 32103760
2008 MCP-1/CCL2: a new diagnostic marker and therapeutic target for progressive renal injury in diabetic nephropathy. American journal of physiology. Renal physiology 357 18272603
2001 Chemokine receptor homo- or heterodimerization activates distinct signaling pathways. The EMBO journal 351 11350939
2005 Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis. Journal of virology 347 15919935
2012 CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Cancer research 343 22472119
2006 CCL2/monocyte chemoattractant protein-1 mediates enhanced transmigration of human immunodeficiency virus (HIV)-infected leukocytes across the blood-brain barrier: a potential mechanism of HIV-CNS invasion and NeuroAIDS. The Journal of neuroscience : the official journal of the Society for Neuroscience 338 16436595
2010 The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. Journal of neuroimmunology 337 20681057
2018 LNMAT1 promotes lymphatic metastasis of bladder cancer via CCL2 dependent macrophage recruitment. Nature communications 336 30237493
1997 Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes. The Journal of experimental medicine 329 9182688
2002 Increased levels of the chemokines GROalpha and MCP-1 in sputum samples from patients with COPD. Thorax 278 12096201
1989 Cloning and sequencing of the cDNA for human monocyte chemotactic and activating factor (MCAF). Biochemical and biophysical research communications 269 2923622
2001 Wound healing in MIP-1alpha(-/-) and MCP-1(-/-) mice. The American journal of pathology 261 11485904
2003 Adiposity elevates plasma MCP-1 levels leading to the increased CD11b-positive monocytes in mice. The Journal of biological chemistry 258 13129912
1996 Increased MCP-1, RANTES, and MIP-1alpha in bronchoalveolar lavage fluid of allergic asthmatic patients. American journal of respiratory and critical care medicine 257 8616572
1990 Properties of monocyte chemotactic and activating factor (MCAF) purified from a human fibrosarcoma cell line. The Journal of experimental medicine 249 2161898
2009 Role of MCP-1 in cardiovascular disease: molecular mechanisms and clinical implications. Clinical science (London, England : 1979) 241 19566488
2018 The chemokine MCP-1 (CCL2) in the host interaction with cancer: a foe or ally? Cellular & molecular immunology 223 29375123
2003 Significant involvement of CCL2 (MCP-1) in inflammatory disorders of the lung. Microcirculation (New York, N.Y. : 1994) 209 12851645
2014 Pro-inflammatory chemokine CCL2 (MCP-1) promotes healing in diabetic wounds by restoring the macrophage response. PloS one 206 24618995
1999 Expression of MCP-1 by reactive astrocytes in demyelinating multiple sclerosis lesions. The American journal of pathology 201 9916917
1999 Clinical significance of MCP-1 levels in BALF and serum in patients with interstitial lung diseases. The European respiratory journal 159 10515417
2007 Spiegelmer inhibition of CCL2/MCP-1 ameliorates lupus nephritis in MRL-(Fas)lpr mice. Journal of the American Society of Nephrology : JASN 152 17625118
2004 Paraoxonase-1 inhibits oxidised LDL-induced MCP-1 production by endothelial cells. Biochemical and biophysical research communications 146 15144891
2014 Impact of MCP-1 in atherosclerosis. Current pharmaceutical design 142 24862889
1999 Renin-angiotensin blockade lowers MCP-1 expression in diabetic rats. Kidney international 141 10469372
1993 MCP-1 mRNA expression in basal keratinocytes of psoriatic lesions. The Journal of investigative dermatology 139 8345212
2009 Astrocyte-derived MCP-1 mediates neuroprotective effects of noradrenaline. The Journal of neuroscience : the official journal of the Society for Neuroscience 123 19129402
2007 Epstein-Barr virus induces MCP-1 secretion by human monocytes via TLR2. Journal of virology 118 17522215
1999 Increased MCP-1 and MIP-1beta in bronchoalveolar lavage fluid of chronic bronchitics. The European respiratory journal 118 10489845
1998 Estradiol suppresses MCP-1 expression In vivo : implications for atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology 114 9763529
2010 Molecular mechanisms involving sigma receptor-mediated induction of MCP-1: implication for increased monocyte transmigration. Blood 109 20354174
2005 Serum levels of the MCP-1 chemokine in patients with ischemic stroke and myocardial infarction. Mediators of inflammation 108 16106105
2005 Secretion of MCP-1/CCL2 by bile duct epithelia induces myofibroblastic transdifferentiation of portal fibroblasts. American journal of physiology. Gastrointestinal and liver physiology 108 16282363
2002 MCP-1 causes leukocyte recruitment and subsequently endotoxemic ileus in rat. American journal of physiology. Gastrointestinal and liver physiology 106 11751168
2010 Neuronal MCP-1 mediates microglia recruitment and neurodegeneration induced by the mild impairment of oxidative metabolism. Brain pathology (Zurich, Switzerland) 105 21029241
2001 Neuronal MCP-1 expression in response to remote nerve injury. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 101 11149670
2012 Linking tumor-associated macrophages, inflammation, and intestinal tumorigenesis: role of MCP-1. American journal of physiology. Gastrointestinal and liver physiology 97 23019193
2016 Senescence-Associated MCP-1 Secretion Is Dependent on a Decline in BMI1 in Human Mesenchymal Stromal Cells. Antioxidants & redox signaling 95 26573462
2008 Role of MCP-1 in endotoxemia and sepsis. International immunopharmacology 87 18442784
2009 MCP-1 antibody treatment enhances damage and impedes repair of the alveolar epithelium in influenza pneumonitis. American journal of respiratory cell and molecular biology 86 19617401
2013 IκBζ is a transcriptional key regulator of CCL2/MCP-1. Journal of immunology (Baltimore, Md. : 1950) 84 23547114
2013 MCP-1 binds to oxidized LDL and is carried by lipoprotein(a) in human plasma. Journal of lipid research 83 23667177
2012 Obese Mexican American children have elevated MCP-1, TNF-α, monocyte concentration, and dyslipidemia. Pediatrics 83 22473371
2000 Increased expression of chemokines (MCP-1, MIP-1alpha, RANTES) after peripheral nerve transection. Journal of the peripheral nervous system : JPNS 82 10905466
2016 Aging and serum MCP-1 are associated with gut microbiome composition in a murine model. PeerJ 80 27069796
2003 Heme: a novel inducer of MCP-1 through HO-dependent and HO-independent mechanisms. American journal of physiology. Renal physiology 75 12556365
1998 Hypoxia down-regulates MCP-1 expression: implications for macrophage distribution in tumors. Journal of leukocyte biology 73 9620670
2007 Mutant MCP-1 therapy inhibits tumor angiogenesis and growth of malignant melanoma in mice. Biochemical and biophysical research communications 72 17991428
1994 Gamma interferon stimulates monocyte chemotactic protein (MCP-1) in human mesangial cells. The Journal of laboratory and clinical medicine 70 8301205
2005 Prostaglandin E2 promotes degranulation-independent release of MCP-1 from mast cells. Journal of leukocyte biology 69 16275896
2011 Differential effects of 1α,25-dihydroxycholecalciferol on MCP-1 and adiponectin production in human white adipocytes. European journal of nutrition 68 21701898
2008 Role of 12/15-lipoxygenase in the expression of MCP-1 in mouse macrophages. American journal of physiology. Heart and circulatory physiology 68 18296557
1998 Chemokines produced by mesothelial cells: huGRO-alpha, IP-10, MCP-1 and RANTES. Clinical and experimental immunology 68 9649190
2008 iPLA2beta: front and center in human monocyte chemotaxis to MCP-1. The Journal of experimental medicine 66 18208975
2002 Role of endothelial MCP-1 in monocyte adhesion to inflamed human endothelium under physiological flow. American journal of physiology. Heart and circulatory physiology 65 12388329
2004 Antiretroviral treatment alters relationship between MCP-1 and neurometabolites in HIV patients. Antiviral therapy 64 15259906
2024 Role of MCP-1 as an inflammatory biomarker in nephropathy. Frontiers in immunology 61 38239353
2023 Notch-mediated hepatocyte MCP-1 secretion causes liver fibrosis. JCI insight 61 36752206
2018 Role of MCP-1 and CCR2 in alcohol neurotoxicity. Pharmacological research 61 30472461
2012 Absence of MCP-1 leads to elevated bone mass via impaired actin ring formation. Journal of cellular physiology 60 21678414
2015 ATF4 is a novel regulator of MCP-1 in microvascular endothelial cells. Journal of inflammation (London, England) 58 25914608
2013 MCP-1 promotes invasion and adhesion of human ovarian cancer cells. Anticancer research 56 24222114
2014 The effect of inflammatory cell-derived MCP-1 loss on neuronal survival during chronic neuroinflammation. Biomaterials 54 24881026
2010 Regulation of MCP-1 chemokine transcription by p53. Molecular cancer 53 20406462
2006 MCP-1 chemokine receptor CCR2 is decreased on circulating monocytes in sporadic amyotrophic lateral sclerosis (sALS). Journal of neuroimmunology 53 16857270
2006 MCP-1 parallels inflammatory and regenerative responses in ischemic muscle. The Journal of surgical research 50 16488443
2011 Endogenous MCP-1 promotes lung inflammation induced by LPS and LTA. Molecular immunology 49 21529952
2009 Regulating MCP-1 diffusion in affinity hydrogels for enhancing immuno-isolation. Journal of controlled release : official journal of the Controlled Release Society 49 19951731
2018 miR-374a Regulates Inflammatory Response in Diabetic Nephropathy by Targeting MCP-1 Expression. Frontiers in pharmacology 48 30147653
2014 MCP-1 stimulates spinal microglia via PI3K/Akt pathway in bone cancer pain. Brain research 48 25555372
1999 Human cytomegalovirus inhibits transcription of the CC chemokine MCP-1 gene. Journal of virology 48 9847345
2017 Urinary MCP-1 as a biomarker for lupus nephritis: a meta-analysis. Zeitschrift fur Rheumatologie 47 27278779
2008 Insulin regulation of MCP-1 in human adipose tissue of obese and lean women. American journal of physiology. Endocrinology and metabolism 47 18270300
2010 IL-8 and MCP-1 induced by excessive orthodontic force mediates odontoclastogenesis in periodontal tissues. Oral diseases 45 21496183
2003 17Beta-estradiol inhibits MCP-1 production in human keratinocytes. The Journal of investigative dermatology 45 12787135
2007 MCP-1 targeting inhibits muscularis macrophage recruitment and intestinal smooth muscle dysfunction in colonic inflammation. American journal of physiology. Cell physiology 44 17977946
2006 Modulation of MCP-1 and iNOS by 50-Hz sinusoidal electromagnetic field. Nitric oxide : biology and chemistry 44 16455275
2004 Adult porcine islets produce MCP-1 and recruit human monocytes in vitro. Xenotransplantation 44 14962280
2002 Existence of a regulatory loop between MCP-1 and TGF-beta in glomerular immune injury. American journal of physiology. Renal physiology 44 12372783
2014 Sulfur compounds block MCP-1 production by Mycoplasma fermentans-infected macrophages through NF-κB inhibition. Journal of translational medicine 43 24886588
2014 Effects of MCP-1 inhibition by bindarit therapy in a rat model of polycystic kidney disease. Nephron 43 25531096
2010 Evaluation of local MCP-1 and IL-12 nanocoatings for infection prevention in open fractures. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 43 19588527
2009 Soy phosphatidylcholine inhibited TLR4-mediated MCP-1 expression in vascular cells. Atherosclerosis 43 19215923
2007 Pneumocystis stimulates MCP-1 production by alveolar epithelial cells through a JNK-dependent mechanism. American journal of physiology. Lung cellular and molecular physiology 43 17307812
2012 RANTES, MCP-1 chemokines and factors describing rheumatoid arthritis. Molecular immunology 42 22750227
2010 Impact of RANTES, MCP-1 and IL-8 in mast cells. Journal of biological regulators and homeostatic agents 41 20385066
2012 Spinal MCP-1 contributes to the development of morphine antinociceptive tolerance in rats. The American journal of the medical sciences 39 23187120
2005 Parenteral iron treatment induces MCP-1 accumulation in plasma, normal kidneys, and in experimental nephropathy. Kidney international 39 16164630
2020 Systemic MCP-1 Levels Derive Mainly From Injured Liver and Are Associated With Complications in Cirrhosis. Frontiers in immunology 37 32218781
2015 Role of MCP-1 in alcohol-induced aggressiveness of colorectal cancer cells. Molecular carcinogenesis 37 26014148
2021 MCP-1 targeting: Shutting off an engine for tumor development. Oncology letters 36 34868363
2018 MCP-1, KC-like and IL-8 as critical mediators of pathogenesis caused by Babesia canis. PloS one 36 29304171
2015 Exercise in pregnancy does not alter gestational weight gain, MCP-1 or leptin in obese women. The Australian & New Zealand journal of obstetrics & gynaecology 36 25688817
2002 Differential production of RANTES and MCP-1 in synovial fluid from the inflamed human knee. Immunology letters 36 11750041
2015 Analysis of urinary TGF-β1, MCP-1, NGAL, and IL-17 as biomarkers for lupus nephritis. Pathophysiology : the official journal of the International Society for Pathophysiology 35 25595582
2010 Plasma levels of MCP-1 and adiponectin in obstructive sleep apnea syndrome. Archives of otolaryngology--head & neck surgery 35 20855682
1999 Increased monocyte MCP-1 production in acute alcoholic hepatitis. Cytokine 35 10547276
2010 MCP-1 promotes mural cell recruitment during angiogenesis in the aortic ring model. Angiogenesis 34 20571857
2006 Renal upregulation of HO-1 reduces albumin-driven MCP-1 production: implications for chronic kidney disease. American journal of physiology. Renal physiology 34 16968890
1999 Synthesis and secretion of MCP-1 by dental follicle cells--implications for tooth eruption. Journal of dental research 34 10576162
2019 MCP-1 mediates ischemia-reperfusion-induced cardiomyocyte apoptosis via MCPIP1 and CaSR. American journal of physiology. Heart and circulatory physiology 33 31774703
2007 D-Psicose inhibits the expression of MCP-1 induced by high-glucose stimulation in HUVECs. Life sciences 33 17655880