Affinage

CCL5

C-C motif chemokine 5 · UniProt P13501

Length
91 aa
Mass
10.0 kDa
Annotated
2026-06-09
100 papers in source corpus 33 papers cited in narrative 33 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

CCL5 (RANTES) is a secreted CC-chemokine that orchestrates leukocyte recruitment, inflammation, and tissue remodeling through receptor engagement coupled to glycosaminoglycan (GAG)-dependent surface presentation (PMID:27091995, PMID:11282909). Structurally, CCL5 polymerizes into rod-shaped, double-helical higher-order oligomers, and oligomerization is functionally separable from GAG binding: oligomers engage GAGs through a positively charged KKWVR motif distinct from the BBXB motif used by monomers/dimers, while NMR shows dimer-GAG contacts also extend to the N loop in a sulfation-dependent manner (PMID:27091995, PMID:25982530). This higher-order assembly is required for the regular, heparan sulfate-dependent filamentous deposition of CCL5 on endothelial surfaces that enables shear-resistant monocyte arrest under flow, with platelet-derived CCL5 immobilized on activated and atherosclerotic endothelium (PMID:25791723, PMID:11282909). The same oligomerization- and GAG-dependent logic governs CCL5-induced T-cell apoptosis (requiring CCR5, its Tyr339, and surface GAGs, with caspase-9/-3 activation and cytochrome c release) and pro-angiogenic activity dependent on syndecan-1/-4 and CD44 and on VEGF secretion (PMID:16807236, PMID:22752444). CCL5 signals canonically through CCR5 (and CCR1/CCR3), where early Ca2+ and JAK/STAT responses are separable from late FAK-dependent polarization and chemotaxis (PMID:10037796), and additionally through a GPCR-independent route via CD44-GAG that assembles a CD44/Src complex activating p44/42 MAPK (PMID:12714503). Downstream of CCR5/CCR1, CCL5 drives migration, invasion, and matrix remodeling across cell types via MEK/ERK/NF-κB-driven αvβ3 integrin induction, PLC/PKCδ/NF-κB-driven MMP-9, and PKCδ/JNK/ERK-driven MMP-1/MMP-13 collagenase activity (PMID:22506069, PMID:19334035, PMID:29093715). Beyond inflammation, CCL5/CCR5 supports hematopoietic stem cell myeloid skewing, megakaryocyte proplatelet formation, hypothalamic insulin signaling and GLUT4 translocation, hippocampal synaptic bioenergetics, and pericyte-driven DNA-PKcs-mediated chemoresistance in glioblastoma (PMID:22289892, PMID:26647394, PMID:27898058, PMID:33931731, PMID:34239070). CCL5 transcription is controlled in a cell-type- and stimulus-specific manner by NF-κB (downstream of Nod1/2, EBV LMP-1, and IL-1), IRF-1, the Ets factor Fli-1, KLF13/RFLAT-1 (translationally regulated in T cells), NFATc3 (downstream of ASIC1a-mediated Ca2+ influx), and Akt-phosphorylated YB-1, while m6A methylation promoted by tristetraprolin destabilizes CCL5 mRNA (PMID:17705131, PMID:15609310, PMID:15228586, PMID:22292067, PMID:25098295, PMID:11138780, PMID:31903118, PMID:24947514, PMID:34877932).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1993 Medium

    Establishing the RANTES gene structure and promoter defined that its expression is cell-type-specific and kinetically distinct, framing the question of which factors drive transcription in each context.

    Evidence Gene sequencing, promoter-luciferase deletion analysis, and Northern blot across T-cell, fibroblast, and epithelial lines

    PMID:7689610

    Open questions at the time
    • Individual transcription factors binding the mapped elements were not identified
    • Kinetic differences between cell types were described but not mechanistically explained
  2. 1998 Low

    Resolving how CCL5 signals in T cells showed a biphasic Ca2+ response, separating a chemotactic G protein phase from a late tyrosine kinase phase linked to TCR/CD3.

    Evidence Ca2+ flux in CD3-sorted Jurkat cells with anti-CD3 stimulation

    PMID:9552000

    Open questions at the time
    • Correlation between CD3 expression and the late phase, not a defined mechanism
    • Molecular link between TCR and CCL5 signaling not established
  3. 2000 Medium

    Identifying RFLAT-1/KLF13 as a translationally regulated activator explained the delayed kinetics of RANTES expression in activated T cells.

    Evidence Promoter characterization and T-cell activation time-course

    PMID:11138780

    Open questions at the time
    • Mechanism of translational control of KLF13 not detailed
    • Cooperation with other promoter factors unresolved
  4. 2001 High

    Demonstrating that platelet-derived RANTES is immobilized on activated endothelium and triggers shear-resistant monocyte arrest connected CCL5 deposition to atherogenic leukocyte recruitment in vivo.

    Evidence Flow chamber video microscopy, Met-RANTES inhibition, ApoE-/- immunohistochemistry, ex vivo carotid perfusion

    PMID:11282909

    Open questions at the time
    • Molecular basis of endothelial immobilization (GAG/oligomer requirement) not yet defined here
    • Receptor mediating arrest not specified
  5. 2002 Medium

    Mapping HIV-1 induction of CCL5 in microglia showed productive replication and Vpr/Nef are required, with p38 acting as a negative regulator.

    Evidence HIV accessory gene mutants, AZT, and p38 inhibitor in primary microglia

    PMID:12359436

    Open questions at the time
    • Direct transcription factor link not established
    • Generalizability beyond microglia unknown
  6. 2003 High

    Discovery of a GPCR-independent CCL5 pathway through CD44-GAG that assembles a CD44/Src complex activating p44/42 MAPK established a receptor-independent signaling axis.

    Evidence Reciprocal Co-IP, CD44 RNAi, MAPK phosphorylation, and HIV infectivity assays

    PMID:12714503

    Open questions at the time
    • Downstream consequences of CD44/Src signaling beyond MAPK and HIV enhancement not mapped
    • Physiological contexts using this pathway not defined
  7. 1999 High

    Pharmacological dissection of CCR5 signaling separated early responses (Ca2+, dimerization, JAK/STAT) from late FAK-dependent polarization and chemotaxis, showing late events are required for migration.

    Evidence CCR5-transfected HEK-293 cells with (AOP)-RANTES and FAK Co-IP and chemotaxis assays

    PMID:10037796

    Open questions at the time
    • Molecular trigger distinguishing early vs late signaling not identified
    • Endogenous receptor context not tested
  8. 2004 Medium

    Defining IL-1/IFNβ induction of CCL5 in astrocytes through NF-κB, p38, JNK, and synergistic ISRE/C/EBPβ complexes identified the cytokine-driven transcriptional circuitry.

    Evidence Promoter-reporter mutants, pathway inhibitors, super-repressor IκBα, and EMSA

    PMID:15228586

    Open questions at the time
    • Relative contribution of each element in vivo not assessed
    • Cell-type specificity beyond astrocytes unresolved
  9. 2005 Medium

    Showing EBV LMP-1 transactivates CCL5 via CTAR domains and NF-κB through defined promoter sites linked viral oncoprotein signaling to CCL5 induction.

    Evidence Promoter-reporter assays with dominant-negative NF-κB pathway constructs

    PMID:15609310

    Open questions at the time
    • In vivo relevance in EBV-associated disease not established
    • Interplay with other LMP-1-induced genes not addressed
  10. 2006 High

    Establishing that CCL5-induced T-cell apoptosis requires CCR5 Tyr339, surface GAGs, and higher-order oligomerization tied the chemokine's structural assembly directly to a death-inducing function.

    Evidence CCR5 and ligand structure-function mutants with caspase and cytochrome c readouts

    PMID:16807236

    Open questions at the time
    • Signaling steps linking oligomerized CCL5 to mitochondrial apoptosis not fully mapped
    • Physiological setting of T-cell killing not defined
  11. 2006 Medium

    Dissecting CCL5/CCR5-evoked Ca2+ signaling in microglia revealed a multi-step JAK/Gi/PI3K/Btk/PLC cascade using cADPR and ADPR as second messengers.

    Evidence Fura-2 imaging with systematic pharmacological inhibition and nucleotide application

    PMID:16547971

    Open questions at the time
    • Direct molecular targets of cADPR/ADPR not identified
    • Functional output of the Ca2+ signal not defined
  12. 2009 Medium

    Characterizing CCL5-driven migration in multiple cancer types established proteoglycan co-receptors (syndecan-1/-4) and PKCδ/NF-κB-driven MMP-9 as effectors of invasion.

    Evidence RNAi of SDC-1/SDC-4 and MMP-9, GAG-binding-deficient CCL5 mutants, and pathway inhibitors in hepatoma and oral cancer cells

    PMID:19334035 PMID:19632304

    Open questions at the time
    • Whether these pathways operate in primary tumors not shown
    • Receptor selectivity (CCR1 vs CCR5) context-dependent
  13. 2009 Low

    Linking CCL5 to macrophage survival and monocyte transmigration in adipose tissue extended its role to metabolic-tissue inflammation.

    Evidence Macrophage apoptosis and transmigration assays with Akt/ERK readouts

    PMID:19893003

    Open questions at the time
    • No genetic validation or deep pathway dissection
    • Receptor mediating the effect not defined
  14. 2012 Medium

    Multiple gain/loss-of-function studies defined CCL5 transcriptional regulators and a hematopoietic role, including IRF-1-driven expression in injured vessels and CCL5-dependent myeloid skewing of HSCs.

    Evidence IRF-1 promoter mapping with p38/MKK3/MK2 dissection in injured arteries; CCL5 overexpression and knockout mice in HSC transplantation

    PMID:22289892 PMID:22292067

    Open questions at the time
    • Direct receptor for the HSC effect not identified
    • Connection between transcriptional control and hematopoietic phenotype not integrated
  15. 2012 Medium

    Showing CCL5/CCR5 induces αvβ3 integrin via MEK/ERK/NF-κB and contributes GAG- and oligomerization-dependent angiogenesis tied receptor signaling and structural assembly to tumor-relevant cell behaviors.

    Evidence siRNA/inhibitor migration assays in osteosarcoma; CCL5 mutants, SDC siRNA, anti-VEGFR antibodies in angiogenesis models

    PMID:22506069 PMID:22752444

    Open questions at the time
    • Integration of GPCR and GAG inputs during angiogenesis unresolved
    • In vivo tumor angiogenesis relevance limited to single models
  16. 2014 Medium

    Identifying Fli-1, Akt-phosphorylated YB-1 (countered by calcineurin), and IL-32θ/PKCδ/STAT3 as regulators expanded the CCL5 transcriptional network and its post-translational control.

    Evidence ChIP, siRNA, promoter-reporter, and Co-IP across endothelial, monocyte, and other systems

    PMID:24947514 PMID:25098295 PMID:25280942

    Open questions at the time
    • Hierarchy among these factors not established
    • Combinatorial control in a single cell type not tested
  17. 2015 High

    High-resolution structural work defined how CCL5 dimers and oligomers contact GAGs and established that filamentous endothelial deposition requires both higher-order oligomerization and heparan sulfate binding.

    Evidence Solution NMR with PRE/NOE constraints; EM/IF/flow chamber with oligomerization and GAG-binding mutants

    PMID:25791723 PMID:25982530

    Open questions at the time
    • Dynamics of polymer assembly on living endothelium not directly observed
    • Link from filament geometry to specific receptor engagement not resolved
  18. 2015 Medium

    Demonstrating that platelet-released CCL5 increases megakaryocyte proplatelet formation and ploidy through CCR5/Akt extended CCL5 function to thrombopoiesis.

    Evidence MK culture with releasate, maraviroc, CCL5 immunodepletion, and an in vivo colitis model

    PMID:26647394

    Open questions at the time
    • Direct CCR5 signaling steps to ploidy not fully mapped
    • Apoptosis-suppression mechanism described as putative
  19. 2016 High

    Crystal/solution structures resolved CCL5 as a polymerizing chemokine forming double-helical oligomers using a KKWVR GAG-binding motif distinct from the monomer/dimer BBXB motif, making oligomerization and GAG binding structurally separable.

    Evidence X-ray crystallography and biophysics with GAG-binding and oligomerization mutants

    PMID:27091995

    Open questions at the time
    • In vivo dependence of each motif on specific functions not exhaustively tested
    • Polymer length regulation not defined
  20. 2016 Medium

    Identifying CCL5/CCR5 as a positive regulator of hypothalamic insulin signaling via PI3K-Akt and AMPKα-S6K modulation of IRS-1 extended CCL5 into central metabolic control.

    Evidence Co-IP of CCR5 with insulin receptor, knockout mice, GLUT4 translocation, and intracerebroventricular Met-CCL5

    PMID:27898058

    Open questions at the time
    • Mechanism of CCR5-insulin receptor cross-talk not structurally defined
    • Relevance to systemic insulin resistance only partly addressed
  21. 2020 Medium

    Establishing the ASIC1a-Ca2+-NFATc3 axis as a direct CCL5 promoter activator linked ion-channel-driven calcium signaling to CCL5 transcription in arthritis.

    Evidence Calcium imaging, ChIP-qPCR, dual-luciferase reporter, and an adjuvant-induced arthritis model

    PMID:31903118

    Open questions at the time
    • Cooperation of NFATc3 with NF-κB at the promoter not dissected
    • Generalizability beyond synovial fibroblasts unknown
  22. 2021 Medium

    Multiple studies expanded CCL5 into matrix degradation, RNA-level control, neuronal bioenergetics, antiviral restriction, and tumor chemoresistance, broadening its mechanistic reach.

    Evidence Collagenase/CD/siRNA in RA fibroblasts (MMP-1/-13); m6A-seq and TTP overexpression; CCL5-KO hippocampal metabolomics and rescue; SAMHD1 knockdown in A549; pericyte depletion and maraviroc in GBM xenografts

    PMID:29093715 PMID:33931731 PMID:34239070 PMID:34490131 PMID:34877932

    Open questions at the time
    • Each role established in a single lab/model
    • Connections among these diverse functions not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CCL5 oligomer geometry, GAG binding, and receptor (CCR1/3/5 vs CD44) engagement are integrated to select among migration, apoptosis, angiogenesis, and metabolic outputs remains unresolved.
  • No unifying model linking structural assembly state to functional output
  • Quantitative receptor occupancy on GAG-immobilized oligomers in vivo not measured
  • Cross-talk between GPCR-dependent and CD44-dependent pathways not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0008289 lipid binding 3
Localization
GO:0005576 extracellular region 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 4 R-HSA-1500931 Cell-Cell communication 2
Partners
CCR1CCR5CD44SDC1SDC4

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 Crystal and solution structures of CCL5 reveal that oligomerization is a polymerization process forming rod-shaped, double-helical oligomers. The CCL5 oligomer uses a positively charged KKWVR motif for glycosaminoglycan (GAG) binding, which is distinct from the partially buried BBXB motif used by monomers/dimers. Oligomerization and GAG binding are structurally separable features of CCL5 function. X-ray crystallography, biophysical analyses, mutational analysis of GAG-binding and oligomerization mutants Proceedings of the National Academy of Sciences of the United States of America High 27091995
2015 NMR structural analysis of CCL5 dimers bound to chondroitin sulfate oligosaccharides shows that, in addition to the BBXB motif in the 40s loop, GAGs also contact residues in the N loop. GAG binding orientation is highly dependent on the sulfation pattern of N-acetylgalactosamine groups. Solution NMR, paramagnetic relaxation enhancement, intermolecular NOE constraints, structural modeling Structure (London, England : 1993) High 25982530
2015 CCL5 binds to the surface of human endothelial cells in a regular filamentous pattern dependent on heparan sulfate. CCL5 mutants restricted in heparin binding, dimerization, or tetramerization failed to form filaments, suggesting that higher-order oligomers and GAG binding are required for physiologically relevant surface presentation and leukocyte recruitment. Immunofluorescence, electron microscopy, flow chamber assay, heparan sulfate-deficient cell lines, CCL5 oligomerization/GAG-binding mutants Scientific reports High 25791723
2001 RANTES/CCL5 secreted by thrombin-stimulated platelets is immobilized on inflamed or atherosclerotic endothelial surfaces and triggers shear-resistant monocyte arrest under flow conditions. This deposition requires endothelial activation (e.g., by IL-1β) and is blocked by the RANTES receptor antagonist Met-RANTES or anti-RANTES antibody. ELISA, immunofluorescence, parallel-wall flow chamber with video microscopy, Met-RANTES/antibody inhibition, immunohistochemistry in ApoE-/- mice, ex vivo carotid artery perfusion Circulation High 11282909
2003 RANTES/CCL5 activates a G protein-coupled receptor (GPCR)-independent signaling pathway through interaction with glycosaminoglycan (GAG) chains of CD44. This RANTES–CD44 association forms a signaling complex containing CD44, Src kinases, and adapter molecules, activating the p44/42 MAPK pathway. CD44 knockdown via RNA interference abolished p44/42 MAPK activation by RANTES and reduced HIV-1 infectivity enhancement. Co-immunoprecipitation, RNA interference (CD44 knockdown), p44/42 MAPK phosphorylation assays, HeLa-CD4 cell HIV infectivity assays Blood High 12714503
1999 CCR5-mediated signaling by RANTES induces early responses (Ca2+ influx, receptor dimerization, tyrosine phosphorylation, Gαi and JAK/STAT association). In contrast to native RANTES, the derivative (AOP)-RANTES fails to trigger late responses including FAK association with the receptor complex, cell polarization, and chemotaxis, demonstrating that late signaling events are separable from early ones and are required for migration. CCR5-transfected HEK-293 cells, Ca2+ flux assays, receptor dimerization assays, tyrosine phosphorylation assays, FAK co-immunoprecipitation, chemotaxis assays The Journal of cell biology High 10037796
2006 CCL5-induced apoptosis in CCR5-expressing T cells requires (1) CCR5 expression, (2) tyrosine 339 of CCR5, (3) cell surface GAG binding (heparin/chondroitin sulfate addition or GAG digestion protects from death), and (4) higher-order CCL5 oligomerization—the non-GAG-binding mutant (44AANA47)-CCL5 and the dimer-restricted E66S mutant fail to induce apoptosis, while tetramer-forming E26A does. Apoptosis involves cytochrome c release, caspase-9 and caspase-3 activation, and PARP cleavage. CCR5-expressing and CCR5-null T cell lines, CCR5 tyrosine mutant (Y339F), GAG-binding CCL5 mutants, oligomerization CCL5 mutants, caspase activity assays, cytochrome c release assay The Journal of biological chemistry High 16807236
2012 CCL5 promotes migration of human osteosarcoma cells through CCR5 (not CCR1 or CCR3) by activating MEK→ERK→NF-κB signaling, which upregulates αvβ3 integrin expression. CCR5 siRNA/antibody/inhibitor and CCL5 shRNA each reduce migration and integrin upregulation. siRNA knockdown, CCR5 antibody, pharmacological inhibitors (MEK, ERK, NF-κB), integrin expression assays, migration assays PloS one Medium 22506069
2009 CCL5-induced migration and invasion of human hepatoma cells through CCR1 requires syndecan-1 (SDC-1) and syndecan-4 (SDC-4) as co-receptors. Antibody blockade or siRNA knockdown of SDC-1 or SDC-4 reduces CCL5-induced chemotaxis and spreading. A GAG-binding-deficient CCL5 mutant (R47K) has no effect, confirming the necessity of chemokine–proteoglycan interaction. Oligomerization interference also reduces CCL5-mediated chemotaxis. Pharmacological inhibitors (FAK, PI3K, MAPK, ROCK), RNA interference (SDC-1, SDC-4), CCL5 oligomerization and GAG-binding mutants, Boyden chamber migration/invasion assays Biochimica et biophysica acta Medium 19632304
2009 CCL5 promotes oral cancer cell migration by inducing MMP-9 expression through CCR5 via activation of PLC→PKCδ→NF-κB signaling. MMP-9 siRNA abrogates CCL5-induced migration, placing MMP-9 downstream of CCL5/CCR5 in this pathway. RT-PCR, flow cytometry, siRNA (MMP-9), specific pharmacological inhibitors (PLC, PKCδ, NF-κB), migration and invasion assays Journal of cellular physiology Medium 19334035
2017 RANTES/CCL5 induces MMP-1 and MMP-13 expression in rheumatoid arthritis synovial fibroblasts (RASFs) through PKCδ, JNK, and ERK signaling, leading to collagenase activity and collagen triple-helix degradation. Heparan sulfate proteoglycan (HSPG) digestion by heparinase III or Met-RANTES pre-treatment completely abrogates MMP induction. CCL5 siRNA also reduces IL-1β-induced MMP expression, placing CCL5 upstream of IL-1β-driven MMP production. 3D micromass culture, collagenase activity assay, circular dichroism spectroscopy, siRNA, Met-RANTES antagonist, heparinase III, specific kinase inhibitors Frontiers in immunology Medium 29093715
2012 Rantes/CCL5 influences hematopoietic stem cell (HSC) subtype distribution and causes myeloid skewing. Forced CCL5 overexpression reduced T-cell output; brief ex vivo CCL5 exposure decreased T-cell progeny and increased myeloid progenitors. CCL5 knockout mice show decreased myeloid-biased HSCs and myeloid progenitors, increased lymphoid-biased HSCs, and decreased mTOR activity in KLS cells. Retroviral overexpression, knockout mice, transplantation assays, flow cytometry, mTOR activity measurement Blood Medium 22289892
2015 CCL5 released by activated platelets (via TRAP stimulation) increases megakaryocyte (MK) proplatelet formation and ploidy through CCR5. Maraviroc (CCR5 antagonist) or CCL5 immunodepletion of platelet releasate abolished most of this effect. Mechanistically, CCL5/CCR5 may increase MK ploidy and proplatelet formation by suppressing apoptosis through the Akt signaling pathway. MK culture with platelet releasate, recombinant CCL5, maraviroc, CCL5 immunodepletion, ploidy measurements, Akt signaling assays, in vivo murine colitis model Blood Medium 26647394
2014 The Fli-1 transcription factor (Ets family) directly binds Ets binding sites in the distal CCL5 promoter and drives CCL5 transcription in a dose-dependent manner. Fli-1 knockdown (siRNA) in endothelial cells significantly decreased CCL5 protein. Ets1 acts as a dominant-negative for Fli-1 at shared binding sites. A 225-bp region of the CCL5 promoter contains the critical Fli-1 binding sites. ChIP, siRNA knockdown, transient transfection with promoter-reporter constructs, promoter deletion and mutation analysis Journal of immunology (Baltimore, Md. : 1950) Medium 25098295
2014 YB-1 phosphorylated at Ser-102 (mediated through Akt signaling) binds the CCL5 promoter with greater affinity and trans-activates CCL5 expression during monocyte differentiation. Calcineurin (CN) dephosphorylates YB-1 at Ser-102, preventing its binding to the CCL5 promoter and thereby downregulating CCL5. Co-immunoprecipitation confirmed a direct YB-1/CN interaction. Co-immunoprecipitation, promoter-reporter assays, Akt pathway inhibitors, calcineurin inhibitor (cyclosporine A), ChIP, in vivo mouse kidney tissue analysis The Journal of biological chemistry Medium 24947514
2007 Activation of Nod1 and Nod2 (intracellular pattern recognition receptors) induces CCL5 secretion in murine macrophages via the NF-κB pathway (not via interferon-β signaling). In vivo, intraperitoneal injection of Nod1 or Nod2 agonists rapidly elevates CCL5 in blood. NF-κB was identified as the key signaling pathway by promoter stimulation assays. Macrophage stimulation assays, in vivo agonist injection, promoter-reporter assays, NF-κB pathway analysis European journal of immunology Medium 17705131
2020 ASIC1a (acid-sensing ion channel 1a) mediates Ca2+ influx in rheumatoid arthritis synovial fibroblasts, which activates NFATc3 nuclear translocation. NFATc3 then directly binds the RANTES/CCL5 promoter and activates CCL5 transcription, as shown by ChIP-qPCR and dual-luciferase reporter assay. Calcium imaging, flow cytometry, ChIP-qPCR, dual-luciferase reporter assay, Western blot, immunofluorescence, adjuvant-induced arthritis rat model Theranostics Medium 31903118
2005 EBV latent membrane protein 1 (LMP-1) transactivates CCL5 expression via both CTAR-1 and CTAR-2 domains through NF-κB signaling. Dominant-negative constructs for IκBα, IκBβ, IKKα, IKKβ, NIK, and TRAF2 inhibited LMP-1-driven CCL5 promoter activation. The NF-κB binding sites (R(A/B)) at positions -71 to -43 of the CCL5 promoter are essential. CCL5 promoter-reporter assays, dominant-negative NF-κB pathway constructs, RT-PCR, ELISA in EBV-infected and EBV-negative cell lines International journal of cancer Medium 15609310
2012 CCL5 expression in vascular smooth muscle cells (SMCs) following arterial injury is mediated by IRF-1 binding to an IRF-1 response element in the CCL5 promoter. p38 MAPK suppresses CCL5 expression through MKK3, and the downstream molecule MK2 selectively mediates p38-dependent CCL5 (but not IP-10) inhibition in SMCs. Balloon artery injury model in rats, SMC culture, promoter-reporter assays, qRT-PCR, pharmacological inhibitors (p38 MAPK, MKK3), MK2 knockdown PloS one Medium 22292067
2004 IL-1 induces RANTES/CCL5 expression in human astrocytes through NF-κB, p38 MAPK, and JNK pathways (but not ERK). IFNβ synergizes with IL-1 by enhancing p38 phosphorylation and by co-inducing nuclear C/EBPβ and ISRE complexes containing Stat1, Stat2, and IRF-1. Mutated promoter-reporter constructs implicated κB, ISRE, and C/EBPβ sites as necessary for IL-1/IFNβ-induced CCL5 transcription. RNase protection assay, ELISA, promoter-reporter constructs with site mutations, pharmacological inhibitors (p38, JNK, ERK), super-repressor IκBα transfection, EMSA for nuclear complexes Journal of neurochemistry Medium 15228586
2002 HIV-1 Vpr and Nef are required for RANTES/CCL5 induction in primary human microglia. Inhibition of reverse transcription (AZT) blocked CCL5 induction, indicating that productive viral replication is necessary. p38 MAPK plays a negative regulatory role (its specific inhibitor SB203580 augmented CCL5 expression). HIV infection of primary microglia with accessory gene mutants, AZT reverse transcriptase inhibitor, p38 MAPK inhibitor (SB203580), RT-PCR and protein assays Virology Medium 12359436
2006 CCL5/CCR5 signaling in microglia activates intracellular Ca2+ elevation through a multi-step pathway requiring JAK activity, inhibitory G protein, PI3K, Bruton's tyrosine kinase, PLC-mediated IP3-sensitive Ca2+ store release, and NAD metabolites (cADPR for intracellular Ca2+ release; ADPR for Ca2+ influx via a nimodipine-sensitive channel). Fura-2 digital imaging of [Ca2+]i, pharmacological inhibitors targeting each step (JAK, Gi, PI3K, Btk, PLC), cADPR and ADPR application, nimodipine block Journal of neuroscience research Medium 16547971
2021 CCL5 secreted by pericytes activates CCR5 on GBM cells to enable DNA-PKcs-mediated DNA damage repair (DDR) upon temozolomide treatment. Disrupting CCL5-CCR5 paracrine signaling with maraviroc inhibits pericyte-promoted DDR and enhances TMZ cytotoxicity in GBM xenografts. Genetic pericyte depletion in xenografts, CCR5 antagonist (maraviroc), DNA-PKcs activity assays, GBM patient-derived xenografts, in vivo survival experiments Cell research Medium 34239070
2016 CCL5/CCR5 promotes angiogenic effects that depend on VEGF secretion by endothelial cells, CCR1 and CCR5 receptor signaling, and GAG (heparan sulfate proteoglycan) binding via SDC-1, SDC-4, and CD44. CCL5 mutants impaired in oligomerization ([E66A]) or GAG binding ([44AANA47]) fail to induce angiogenic effects in vitro and in vivo, establishing that both oligomerization and GAG binding are required for RANTES/CCL5-induced angiogenesis. In vitro endothelial migration/spreading/tube formation assays, in vivo rat subcutaneous neovascularization model, anti-VEGF receptor antibodies, CCL5 mutants ([E66A], [44AANA47]), siRNA for SDC-1/SDC-4, MMP-9 activity assays Angiogenesis Medium 22752444
2014 IL-32θ downregulates CCL5 expression by interacting with PKCδ and STAT3. This interaction leads to STAT3 phosphorylation at Ser727, rendering STAT3 transcriptionally inactive at the CCL5 promoter. Co-IP and pulldown assays confirmed direct IL-32θ/PKCδ and IL-32θ/STAT3 interactions. Co-immunoprecipitation, pulldown assay, ELISA, STAT3 Ser727 phosphorylation assay, ChIP for STAT3 at CCL5 promoter Cellular signalling Medium 25280942
2021 Tristetraprolin (TTP) promotes N6-methyladenosine (m6A) methylation on CCL5 mRNA, destabilizing it and reducing CCL5 levels. TTP overexpression upregulates m6A methylation enzymes (WTAP, METTL14, YTHDF2), globally increasing m6A and specifically decreasing CCL5 mRNA stability, ameliorating acute liver failure in vivo. m6A sequencing, RNA stability assays, TTP overexpression in vivo, methyltransferase expression analysis, in vivo murine acute liver failure model JCI insight Medium 34877932
2016 CCL5/RANTES contributes to hypothalamic insulin signaling through CCR5, which co-localizes and co-immunoprecipitates with insulin receptors in the arcuate nucleus. CCL5/CCR5 activates the PI3K-Akt pathway and reduces inhibitory phosphorylation of IRS-1 at Ser302 via AMPKα-S6 kinase signaling, promoting GLUT4 membrane translocation. Intracerebroventricular Met-CCL5 blocks hypothalamic insulin signaling and induces peripheral glucose intolerance. Co-immunoprecipitation, immunostaining, ex vivo and in vitro stimulation assays, CCR5/CCL5 knockout mice, GLUT4 translocation assay, intracerebroventricular drug delivery Scientific reports Medium 27898058
2021 CCL5 supports hippocampal synaptic function and memory formation by promoting bioenergy metabolism: fructose/mannose degradation, glycolysis, gluconeogenesis, glutamate and purine metabolism, ATP generation, and mitochondrial structural integrity. Re-expressing CCL5 in CCL5-knockout mouse hippocampus restored synaptic protein expression, neuronal connectivity, and cognitive function. CCL5 knockout mice, hippocampal LTP measurement, metabolomics, FDG-PET imaging, Seahorse metabolic analysis, AAV re-expression, behavioral assays Molecular psychiatry Medium 33931731
2000 RANTES expression in T lymphocytes requires the Krüppel-like transcription factor RFLAT-1 (KLF13), which is itself expressed late after T-cell activation. Uniquely, RFLAT-1 expression is translationally rather than transcriptionally regulated, explaining the 3–5 day delayed kinetics of RANTES expression in activated T cells. Promoter characterization, transcription factor identification and characterization, T-cell activation time-course experiments Immunological reviews Medium 11138780
1993 The RANTES gene spans ~7.1 kb with three exons and two introns, and has a 1-kb promoter containing consensus elements for T cell/hematopoietic, myeloid, muscle, and ubiquitous transcription factors. Promoter-luciferase assays and deletion analysis show that different transcriptional mechanisms regulate RANTES expression in different cell types (e.g., high in mature T cells Hut78 but not in early T cell lines), and that the kinetics of RANTES mRNA expression differ between cell types (late in T cells, early in fibroblasts/epithelial cells after TNF-α). Gene sequencing, promoter-luciferase reporter assays, deletion analysis, Northern blot Journal of immunology (Baltimore, Md. : 1950) Medium 7689610
2021 CCL5 inhibits influenza A virus (IAV) replication in alveolar epithelial cells by upregulating the restriction factor SAMHD1. CCL5-mediated SAMHD1 upregulation is dependent on PKC signaling. SAMHD1 knockdown abolishes both CCL5-mediated IAV inhibition and CCL5-mediated cell death inhibition. A549 cell CCR5 stimulation with CCL5, RT-PCR restriction factor panel, siRNA knockdown of SAMHD1, PKC inhibition, viral titer assays Frontiers in cellular and infection microbiology Low 34490131
1998 RANTES induces a biphasic Ca2+ signal in T cells: an early G protein-mediated phase associated with chemotaxis, and a late tyrosine kinase-linked phase unique to RANTES. The late phase correlates with CD3 expression on Jurkat T cells, and prior TCR stimulation with anti-CD3 suppresses the RANTES-induced second phase, suggesting TCR involvement. Ca2+ flux measurements, Jurkat cell sorting by CD3 expression, anti-CD3 mAb stimulation, comparison of CD3-high vs. CD3-low populations Journal of immunology (Baltimore, Md. : 1950) Low 9552000
2009 CCL5 promotes macrophage survival in adipose tissue by protecting macrophages from free cholesterol-induced apoptosis via activation of Akt and ERK pathways. CCL5 also triggers adhesion and transmigration of blood monocytes through adipose tissue endothelial cells. Macrophage apoptosis assays (free cholesterol model), Akt/ERK pathway activation assays, monocyte transmigration assay through adipose tissue endothelial cells Arteriosclerosis, thrombosis, and vascular biology Low 19893003

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer letters 483 18439751
2001 RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation 464 11282909
2014 The inflammatory chemokine CCL5 and cancer progression. Mediators of inflammation 355 24523569
2020 The CCL5/CCR5 Axis in Cancer Progression. Cancers 313 32630699
2013 Targeting CCL5 in inflammation. Expert opinion on therapeutic targets 312 24090198
2021 CCL5/CCR5 axis in human diseases and related treatments. Genes & diseases 276 34514075
1993 Genomic organization and transcriptional regulation of the RANTES chemokine gene. Journal of immunology (Baltimore, Md. : 1950) 258 7689610
2012 Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing. Blood 228 22289892
2001 MCP-1 and RANTES are mediators of acute and chronic inflammation. Allergy and asthma proceedings 219 11424873
2002 Chemokine RANTES in severe pulmonary arterial hypertension. American journal of respiratory and critical care medicine 207 11850348
2006 Expression of CCL5 (RANTES) and CCR5 in prostate cancer. The Prostate 197 16161154
2015 CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 184 25901081
2009 CCL5 promotes macrophage recruitment and survival in human adipose tissue. Arteriosclerosis, thrombosis, and vascular biology 181 19893003
2021 Pericytes augment glioblastoma cell resistance to temozolomide through CCL5-CCR5 paracrine signaling. Cell research 134 34239070
2007 Mechanisms of disease: regulation of RANTES (CCL5) in renal disease. Nature clinical practice. Nephrology 116 17322928
2006 Role of CCL5 (RANTES) in viral lung disease. Journal of virology 111 16873271
1996 RANTES chemokine expression in transplant-associated accelerated atherosclerosis. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 109 8981204
1998 RANTES expression and contribution to monocyte chemotaxis in arthritis. Clinical immunology and immunopathology 107 9756723
2003 RANTES (CCL5) uses the proteoglycan CD44 as an auxiliary receptor to mediate cellular activation signals and HIV-1 enhancement. Blood 100 12714503
1999 Similarities and differences in RANTES- and (AOP)-RANTES-triggered signals: implications for chemotaxis. The Journal of cell biology 100 10037796
2017 RANTES/CCL5 Induces Collagen Degradation by Activating MMP-1 and MMP-13 Expression in Human Rheumatoid Arthritis Synovial Fibroblasts. Frontiers in immunology 96 29093715
2009 CCL5/CCR5 axis promotes the motility of human oral cancer cells. Journal of cellular physiology 96 19334035
2003 Expression of CCL5/RANTES by Hodgkin and Reed-Sternberg cells and its possible role in the recruitment of mast cells into lymphomatous tissue. International journal of cancer 96 12949794
2015 CCL5 derived from platelets increases megakaryocyte proplatelet formation. Blood 95 26647394
2014 The potential to target CCL5/CCR5 in breast cancer. Expert opinion on therapeutic targets 94 25256399
1998 RANTES expression in psoriatic skin, and regulation of RANTES and IL-8 production in cultured epidermal keratinocytes by active vitamin D3 (tacalcitol). The British journal of dermatology 93 9536224
2009 Chemokine CCL5/RANTES inhibition reduces myocardial reperfusion injury in atherosclerotic mice. Journal of molecular and cellular cardiology 92 19665464
2012 CCL5 and CCR5 interaction promotes cell motility in human osteosarcoma. PloS one 88 22506069
2012 RANTES/CCL5-induced pro-angiogenic effects depend on CCR1, CCR5 and glycosaminoglycans. Angiogenesis 85 22752444
2016 Functional role of CCL5/RANTES for HCC progression during chronic liver disease. Journal of hepatology 82 28011329
2020 Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19. medRxiv : the preprint server for health sciences 81 32511656
1996 RANTES chemokine expression in diseased and normal human tissues. Cytokine 81 8742071
2014 CCL5/RANTES is a key chemoattractant released by degenerative intervertebral discs in organ culture. European cells & materials 77 24500793
2010 CCL5 as an adjuvant for cancer immunotherapy. Expert opinion on biological therapy 77 20233026
2000 Transcriptional regulation of RANTES expression in T lymphocytes. Immunological reviews 77 11138780
1990 Localization of a human T-cell-specific gene, RANTES (D17S136E), to chromosome 17q11.2-q12. Genomics 72 1691736
2007 Nod1 and Nod2 induce CCL5/RANTES through the NF-kappaB pathway. European journal of immunology 69 17705131
2011 Angiogenic properties of the chemokine RANTES/CCL5. Biochemical Society transactions 67 22103502
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
2000 Inducible lung-specific expression of RANTES: preferential recruitment of neutrophils. American journal of physiology. Lung cellular and molecular physiology 66 11000125
1996 Induction of RANTES expression by astrocytes and astrocytoma cell lines. Journal of neuroimmunology 66 8982121
2007 CCR1/CCL5 (RANTES) receptor-ligand interactions modulate allogeneic T-cell responses and graft-versus-host disease following stem-cell transplantation. Blood 65 17641205
2019 Cytokine CCL5 and receptor CCR5 axis in glioblastoma multiforme. Radiology and oncology 63 31747383
2001 RANTES-induced chemokine cascade in dendritic cells. Journal of immunology (Baltimore, Md. : 1950) 63 11466387
2006 CCL5-CCR5-mediated apoptosis in T cells: Requirement for glycosaminoglycan binding and CCL5 aggregation. The Journal of biological chemistry 62 16807236
2020 ASIC1a induces synovial inflammation via the Ca2+/NFATc3/ RANTES pathway. Theranostics 61 31903118
2015 Recent Advances in Discovering the Role of CCL5 in Metastatic Breast Cancer. Mini reviews in medicinal chemistry 61 26420723
2015 RANTES and SDF-1 Are Keys in Cell-based Therapy of TMJ Osteoarthritis. Journal of dental research 60 26377571
2017 Misbalanced CXCL12 and CCL5 Chemotactic Signals in Vitiligo Onset and Progression. The Journal of investigative dermatology 54 28132854
2002 RANTES stimulates inflammatory cascades and receptor modulation in murine astrocytes. Glia 53 12112372
1997 Switching gears during T-cell maturation: RANTES and late transcription. Immunology today 53 9357137
2004 Regulation of RANTES/CCL5 expression in human astrocytes by interleukin-1 and interferon-beta. Journal of neurochemistry 51 15228586
2008 CCL5/RANTES gene deletion attenuates opioid-induced increases in glial CCL2/MCP-1 immunoreactivity and activation in HIV-1 Tat-exposed mice. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 47 18815890
2001 Rantes production during development of cardiac allograft vasculopathy. Transplantation 47 11435978
2023 Chordoma recruits and polarizes tumor-associated macrophages via secreting CCL5 to promote malignant progression. Journal for immunotherapy of cancer 46 37185233
2020 EZH2 enhances expression of CCL5 to promote recruitment of macrophages and invasion in lung cancer. Biotechnology and applied biochemistry 44 31855281
2016 RANTES correlates with inflammatory activity and synaptic excitability in multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England) 44 26733422
2009 Syndecan-1 and syndecan-4 are involved in RANTES/CCL5-induced migration and invasion of human hepatoma cells. Biochimica et biophysica acta 44 19632304
2002 Expression of the chemokines MCP-1/CCL2 and RANTES/CCL5 is differentially regulated by infiltrating inflammatory cells. Kidney international 43 12234296
2022 Macrophages-aPKCɩ-CCL5 Feedback Loop Modulates the Progression and Chemoresistance in Cholangiocarcinoma. Journal of experimental & clinical cancer research : CR 42 35033156
2011 RANTES/CCL5 and risk for coronary events: results from the MONICA/KORA Augsburg case-cohort, Athero-Express and CARDIoGRAM studies. PloS one 42 22162987
2002 Vpr- and Nef-dependent induction of RANTES/CCL5 in microglial cells. Virology 42 12359436
1997 Regulation of RANTES and ICAM-1 expression in murine mesangial cells. Journal of the American Society of Nephrology : JASN 42 10495789
1998 RANTES-induced T cell activation correlates with CD3 expression. Journal of immunology (Baltimore, Md. : 1950) 41 9552000
2016 CCL5/RANTES contributes to hypothalamic insulin signaling for systemic insulin responsiveness through CCR5. Scientific reports 40 27898058
2021 Tumor Extracellular Vesicles Regulate Macrophage-Driven Metastasis through CCL5. Cancers 39 34298673
2015 Interactions of the Chemokine CCL5/RANTES with Medium-Sized Chondroitin Sulfate Ligands. Structure (London, England : 1993) 39 25982530
2021 CCL5 promotion of bioenergy metabolism is crucial for hippocampal synapse complex and memory formation. Molecular psychiatry 38 33931731
2018 Osteoimmunology of tumor necrosis factor-alpha, IL-6, and RANTES/CCL5: a review of known and poorly understood inflammatory patterns in osteonecrosis. Clinical, cosmetic and investigational dentistry 38 30519117
2014 CCL5/RANTES is important for inducing osteogenesis of human mesenchymal stem cells and is regulated by dexamethasone. Bioscience trends 37 25030847
2014 The Fli-1 transcription factor regulates the expression of CCL5/RANTES. Journal of immunology (Baltimore, Md. : 1950) 37 25098295
2011 IκBα glutathionylation and reduced histone H3 phosphorylation inhibit eotaxin and RANTES. The European respiratory journal 36 21719482
2022 Targeting CCL5 signaling attenuates neuroinflammation after seizure. CNS neuroscience & therapeutics 35 36440924
2014 Calcineurin-mediated YB-1 dephosphorylation regulates CCL5 expression during monocyte differentiation. The Journal of biological chemistry 35 24947514
2012 Induction of IL-6 and CCL5 (RANTES) in human respiratory epithelial (A549) cells by clinical isolates of respiratory syncytial virus is strain specific. Virology journal 35 22962966
2008 RANTES/CCL5 gene polymorphisms, serum concentrations, and incident type 2 diabetes: results from the MONICA/KORA Augsburg case-cohort study, 1984-2002. European journal of endocrinology 35 18426815
2006 CCL5 modulates pneumococcal immunity and carriage. Journal of immunology (Baltimore, Md. : 1950) 33 16455992
2006 RANTES (CCL5) regulates airway responsiveness after repeated allergen challenge. American journal of respiratory cell and molecular biology 33 16528011
2005 IL-17 reduces TNF-induced Rantes and VCAM-1 expression. Cytokine 33 15975820
2016 Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer. Oncotarget 32 27863423
2011 Decreased mRNA expression of CCL5 [RANTES] in Alzheimer's disease blood samples. Clinical chemistry and laboratory medicine 32 21942811
2024 Integrin β8 Facilitates Macrophage Infiltration and Polarization by Regulating CCL5 to Promote LUAD Progression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 31 39535362
2021 Neddylation pathway alleviates chronic pancreatitis by reducing HIF1α-CCL5-dependent macrophage infiltration. Cell death & disease 31 33723230
2006 CCL5 evokes calcium signals in microglia through a kinase-, phosphoinositide-, and nucleotide-dependent mechanism. Journal of neuroscience research 30 16547971
2005 The expression of RANTES and chemokine receptors in the brains of scrapie-infected mice. Journal of neuroimmunology 30 15589034
2021 TTP protects against acute liver failure by regulating CCL2 and CCL5 through m6A RNA methylation. JCI insight 29 34877932
2014 IL-32θ downregulates CCL5 expression through its interaction with PKCδ and STAT3. Cellular signalling 29 25280942
2020 Arenavirus Induced CCL5 Expression Causes NK Cell-Mediated Melanoma Regression. Frontiers in immunology 28 32973762
2007 Expression of RANTES and MCP-1 in epithelial cells is regulated via LMP1 and CD40. International journal of cancer 28 17721998
2004 Recombinant guinea pig CCL5 (RANTES) differentially modulates cytokine production in alveolar and peritoneal macrophages. Journal of leukocyte biology 28 15377675
2023 The intricate role of CCL5/CCR5 axis in Alzheimer disease. Journal of neuropathology and experimental neurology 26 37769321
2021 Research Trends and Regulation of CCL5 in Prostate Cancer. OncoTargets and therapy 26 33664576
2021 Role of myeloid-derived chemokine CCL5/RANTES at an early stage of atherosclerosis. Journal of molecular and cellular cardiology 26 33781821
2015 Oligomerized, filamentous surface presentation of RANTES/CCL5 on vascular endothelial cells. Scientific reports 25 25791723
2008 CCL5 regulation of mucosal chlamydial immunity and infection. BMC microbiology 25 18700040
2021 The Chemokine CCL5 Inhibits the Replication of Influenza A Virus Through SAMHD1 Modulation. Frontiers in cellular and infection microbiology 24 34490131
2011 CCL5 (RANTES) gene polymorphisms in pulmonary tuberculosis patients of south India. International journal of immunogenetics 24 21707929
2012 Regulation of CCL5 expression in smooth muscle cells following arterial injury. PloS one 23 22292067
2005 Transactivation of the CCL5/RANTES gene by Epstein-Barr virus latent membrane protein 1. International journal of cancer 23 15609310
2003 Intrapulmonary targeting of RANTES/CCL5-responsive cells prevents chronic fungal asthma. European journal of immunology 23 14579276

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