Affinage

CXCL8

Interleukin-8 · UniProt P10145

Round 2 corrected
Length
99 aa
Mass
11.1 kDa
Annotated
2026-04-28
130 papers in source corpus 39 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CXCL8 (interleukin-8) is a prototypical ELR+ CXC chemokine that functions as the principal neutrophil chemoattractant and activator while simultaneously acting as a potent pro-angiogenic factor and autocrine tumor growth signal. Secreted by monocytes, macrophages, epithelial cells, and tumor cells in response to IL-1, TNF, LPS, thrombin, and oncogenic Ras—through NF-κB-dependent transcription regulated by upstream IL-1R/IRAK1, PAR1/PKCα/c-Src/IKK, DCLK1/RhoA/YAP–p65, and Notch1 pathways—CXCL8 signals through two GPCRs: the IL-8-selective CXCR1 and the promiscuous CXCR2, coupling to Gαi/Ca²⁺, PI3K/AKT, ERK, p38 MAPK, and β-arrestin to drive neutrophil chemotaxis, degranulation, respiratory burst, and endothelial cell survival, proliferation, and tube formation (PMID:3480540, PMID:1840701, PMID:8702798, PMID:1281554, PMID:12496258). Its bioactivity is fine-tuned post-translationally: N-terminal truncation by MMP-9 generates the 10–27-fold more potent CXCL8(7-77), whereas citrullination at Arg5 by peptidylarginine deiminase reduces GAG binding, CXCR2 signaling, and in vivo neutrophil recruitment (PMID:11023497, PMID:18710930, PMID:30486423). CXCL8 is transcytosed across venular endothelium via its GAG-binding C-terminus for luminal presentation to leukocytes, a process antagonized by TSG-6 binding (PMID:9363947, PMID:24501198). In cancer, CXCL8 sustains glioblastoma stem cell mesenchymal identity through PI3K/AKT and NF-κB, polarizes tumor-associated macrophages via CXCR2–JAK2/STAT3, and drives myelofibrosis through CXCR2-dependent hematopoietic stem cell expansion and bone marrow fibrosis (PMID:37439870, PMID:36800567).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1987 High

    The discovery of CXCL8 as a distinct neutrophil-specific chemoattractant produced by LPS-stimulated monocytes established it as a novel mediator separate from complement factors and lipid mediators, answering the question of what soluble factor selectively recruits neutrophils during inflammation.

    Evidence Purification to homogeneity from monocyte conditioned medium with chemotaxis assays showing neutrophil but not monocyte activity

    PMID:3322281 PMID:3480540

    Open questions at the time
    • Receptor identity unknown
    • In vivo relevance not yet established
    • Gene structure not yet determined
  2. 1988 High

    Molecular cloning of the CXCL8 cDNA revealed a 99-amino-acid precursor with signal peptide processing and rapid mRNA induction by IL-1, TNF, and LPS but not interferons, establishing CXCL8 as an immediate-early inflammatory gene with defined transcriptional inducers.

    Evidence cDNA cloning from LPS-stimulated monocytes with Northern blot kinetics of mRNA induction

    PMID:3260265

    Open questions at the time
    • Promoter elements responsible for inducibility not yet mapped
    • Post-translational processing details unknown
  3. 1989 High

    Identification of high-affinity CXCL8-binding receptors on neutrophils (~20,000 sites/cell, Kd ~0.8 nM) distinct from all known chemoattractant receptors, together with demonstration that CXCL8 also attracts T lymphocytes in vivo, expanded the target cell repertoire and established receptor-mediated signaling as the basis for CXCL8 activity.

    Evidence Radioligand binding, Scatchard analysis, chemical cross-linking on neutrophils; in vivo rat intradermal injection with lymphocyte/neutrophil quantification

    PMID:2647892 PMID:2648569

    Open questions at the time
    • Molecular identity of receptors unknown
    • Signaling pathways downstream of binding not characterized
  4. 1990 High

    Determination of the CXCL8 dimer structure by NMR and mapping of the gene to chromosome 4q12–q21 within the CXC chemokine cluster provided the structural and genomic framework, revealing the antiparallel α-helix/β-sheet architecture and its evolutionary relationship to the PF4 superfamily.

    Evidence NMR spectroscopy with 1880 distance restraints; somatic cell hybrid mapping and in situ hybridization

    PMID:1967588 PMID:2184886

    Open questions at the time
    • Monomer vs. dimer activity not resolved
    • Structure of receptor-bound CXCL8 unknown
  5. 1991 High

    Cloning of CXCR1 (IL-8RA) as a GPCR with high-affinity IL-8 binding and calcium mobilization in transfected cells answered the fundamental question of receptor identity and established the GPCR/Gαi signaling paradigm for CXCL8.

    Evidence Expression cloning from neutrophil cDNA library, radioligand binding and calcium flux in transfected mammalian cells

    PMID:1840701

    Open questions at the time
    • Second receptor (CXCR2) selectivity profile not yet defined
    • Downstream signaling cascades not mapped
  6. 1992 High

    The demonstration that CXCL8 is a potent angiogenic factor—inducing endothelial proliferation, chemotaxis, and neovascularization in the rat cornea—revealed a second major biological function beyond neutrophil chemotaxis.

    Evidence Rat cornea angiogenesis assay, HUVEC proliferation/chemotaxis, anti-IL-8 antibody and antisense oligonucleotide blockade

    PMID:1281554

    Open questions at the time
    • Receptor subtype mediating angiogenesis unknown
    • Signaling pathways in endothelial cells not defined
  7. 1996 High

    Pharmacological characterization of CXCR1 vs. CXCR2 selectivity resolved how CXCL8 signals through two receptors with distinct ligand profiles: CXCR1 is IL-8-selective while CXCR2 is promiscuous for ELR+ CXC chemokines.

    Evidence Quantitative calcium flux and competitive radioligand binding in HEK293 cells transfected with individual receptors

    PMID:8702798

    Open questions at the time
    • Receptor subtype-specific downstream effectors not dissected
    • In vivo receptor subtype contributions unclear
  8. 1997 High

    Discovery that CXCL8 is transcytosed across venular endothelium and presented luminally via its GAG-binding C-terminus resolved how a subendothelially produced chemokine reaches and activates intravascular leukocytes, establishing the transcytosis–immobilization paradigm for chemokine biology.

    Evidence Electron microscopy of transcytosis, C-terminal deletion mutants lacking GAG binding, in vivo leukocyte emigration assay

    PMID:9363947

    Open questions at the time
    • Vesicular machinery for transcytosis unidentified
    • Proteoglycan identity on luminal surface unknown
  9. 2000 High

    Identification of MMP-9-mediated N-terminal truncation generating the 10–27-fold more potent CXCL8(7-77) established a positive feedback amplification loop at inflammatory sites where neutrophil degranulation potentiates the chemokine that recruited them.

    Evidence In vitro MMP-9 cleavage with neutrophil Ca²⁺ flux, chemotaxis, degranulation, and receptor binding assays on CXCR1/CXCR2-transfected cells

    PMID:11023497

    Open questions at the time
    • In vivo ratio of CXCL8 proteoforms during inflammation not quantified
    • Other proteases generating truncated forms not systematically assessed
  10. 2002 High

    Attribution of CXCL8-driven angiogenesis specifically to CXCR2 (with ERK1/2 and PI3K as required effectors) in primary microvascular endothelial cells resolved which receptor subtype mediates the pro-angiogenic program.

    Evidence HIMEC expressing CXCR2 but not CXCR1; neutralizing antibodies, ERK and PI3K inhibitors blocking tube formation and chemotaxis

    PMID:12496258

    Open questions at the time
    • CXCR1 contribution to angiogenesis in other vascular beds not excluded
    • Transcriptional targets downstream of ERK/PI3K in endothelial cells not mapped
  11. 2004 High

    Demonstration that oncogenic Ras drives CXCL8 transcription and that CXCL8 is required for Ras-dependent tumor angiogenesis and inflammation repositioned CXCL8 as a critical effector of oncogene-driven tumor progression, while receptor-specific studies showed CXCR1-mediated autocrine growth in lung cancer.

    Evidence Tumor xenograft rescue with ectopic CXCL8 in Ras-impaired cells; selective CXCR1/CXCR2 neutralizing antibodies in NSCLC proliferation assays

    PMID:15542429 PMID:15545974

    Open questions at the time
    • Transcription factor(s) linking Ras to CXCL8 promoter not fully defined
    • Autocrine loop contribution vs. paracrine angiogenic role not separated in vivo
  12. 2008 High

    Discovery that PAD-mediated citrullination at Arg5 dampens GAG binding, CXCR2 signaling, and in vivo neutrophil recruitment—while also blocking N-terminal truncation to more active forms—revealed a post-translational brake that fine-tunes CXCL8 bioactivity at inflamed sites.

    Evidence PAD citrullination in vitro, mass spectrometry of natural leukocyte CXCL8, GAG/receptor signaling assays, thrombin/plasmin resistance, in vivo peritoneal recruitment

    PMID:18710930

    Open questions at the time
    • Physiological conditions controlling PAD access to CXCL8 unknown
    • Relative abundance of citrullinated vs. unmodified CXCL8 in human disease tissues not quantified
  13. 2009 High

    Identification of surface-bound IL-1α/IRAK1/NF-κB as the upstream cascade driving senescence-associated CXCL8 secretion, negatively regulated by miR-146a/b targeting IRAK1, linked CXCL8 to the senescence-associated secretory phenotype and its regulation by a microRNA feedback loop.

    Evidence IL-1Rα, neutralizing antibodies, and IL-1α/IRAK1 RNAi suppressed senescence-associated IL-8; ectopic miR-146a/b suppressed IL-8 via IRAK1 depletion

    PMID:19805069 PMID:20148189

    Open questions at the time
    • Other miRNAs directly targeting CXCL8 mRNA not systematically evaluated
    • In vivo relevance of miR-146a–CXCL8 axis in aging tissues not established at this time
  14. 2014 High

    Identification of TSG-6 as a soluble antagonist that binds the CXCL8 GAG-binding site with nanomolar affinity and blocks transcytosis and neutrophil chemotaxis revealed a physiological counter-regulatory mechanism for CXCL8 presentation and activity.

    Evidence SPR (Kd ~25 nM), heparin competition, transendothelial transcytosis blockade, chemotaxis inhibition

    PMID:24501198

    Open questions at the time
    • In vivo relevance of TSG-6-CXCL8 interaction in resolving inflammation not tested
    • Whether TSG-6 antagonizes other CXC chemokines not systematically assessed
  15. 2018 High

    Quantitative dissection of how citrullination and N-terminal truncation modulate Gαi signaling vs. β-arrestin recruitment to CXCR1 and CXCR2 showed that these post-translational modifications alter signaling magnitude at each receptor without inducing biased agonism, refining the model of CXCL8 proteoform-specific signaling.

    Evidence Synthetic CXCL8 variants tested by HTRF (Gαi) and BRET (β-arrestin 1/2) with quantitative dose-response curves

    PMID:30486423

    Open questions at the time
    • Functional consequences of β-arrestin recruitment differences in vivo unknown
    • Whether additional post-translational modifications (e.g. oxidation) alter bias not tested
  16. 2022 High

    Mapping of a DCLK1/RhoA/YAP–p65 transcriptional cascade driving CXCL8 expression in thrombin-stimulated epithelial cells, with ChIP confirming YAP and p65 co-occupancy at the CXCL8 NF-κB site, revealed a non-canonical mechanotransduction input to CXCL8 transcription.

    Evidence ChIP of YAP/p65 at IL-8 promoter, DCLK1 and YAP siRNA epistasis, κB-luciferase reporter, in vivo asthma model validation

    PMID:36369000

    Open questions at the time
    • Whether YAP-p65 co-regulation of CXCL8 operates in cell types beyond lung epithelium not tested
    • Contribution relative to canonical NF-κB activation unknown
  17. 2023 High

    Demonstration that CXCL8 operates through dual cell-intrinsic (PI3K/AKT, NF-κB maintaining cancer stemness) and cell-extrinsic (CXCR2–JAK2/STAT3 polarizing immunosuppressive TAMs) axes in glioblastoma, and that CXCL8/CXCR2 signaling drives bone marrow fibrosis in myelofibrosis, broadened the disease-relevant roles of CXCL8 beyond solid tumor angiogenesis.

    Evidence Patient-derived GSC xenografts with CXCL8/CXCR2 knockdown and combined pathway inhibition; Cxcr2 KO in murine MF model with pharmacological CXCR1/2 inhibition synergizing with JAK inhibitor

    PMID:36800567 PMID:37439870

    Open questions at the time
    • Relative contributions of autocrine vs. paracrine CXCL8 in GBM microenvironment not fully resolved
    • Whether CXCR1 contributes to MF pathology independently of CXCR2 not tested
    • Clinical efficacy of CXCR2 inhibition in myelofibrosis awaits trial data

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of CXCL8 binding to CXCR1 vs. CXCR2 at atomic resolution, the identity of the vesicular machinery mediating CXCL8 transcytosis, the quantitative proteoform landscape of CXCL8 at inflammatory sites in vivo, and whether therapeutic CXCL8 neutralization or receptor blockade can be safely deployed without compromising host defense.
  • No high-resolution structure of CXCL8–CXCR1 or CXCL8–CXCR2 complex available
  • Transcytosis vesicle identity and regulatory machinery undefined
  • Relative proteoform abundances in human disease tissues not quantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 7 GO:0098631 cell adhesion mediator activity 4
Localization
GO:0005576 extracellular region 8
Pathway
R-HSA-168256 Immune System 9 R-HSA-1643685 Disease 5 R-HSA-1500931 Cell-Cell communication 3
Partners
CXCR1CXCR2MMP9SDC4TNFAIP6

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1987 CXCL8 (MDNCF/NAF/IL-8) was purified from LPS-stimulated human monocyte conditioned medium as a 7-kDa protein that acts as a potent and specific neutrophil chemoattractant, with activity comparable to fMet-Leu-Phe, but without chemotactic activity toward monocytes. Protein purification (anion-exchange, gel filtration, HPLC), chemotaxis assay, SDS-PAGE Proceedings of the National Academy of Sciences of the United States of America High 3322281 3480540
1988 The cDNA for CXCL8 (MDNCF) was cloned from LPS-stimulated human monocytes, encoding a 99-aa precursor with a signal sequence; mature protein begins at Ser-28 (72 aa). MDNCF mRNA was induced >10-fold within 1 h by LPS, IL-1, or TNF, but not by IFN-γ, IFN-α, or IL-2. cDNA cloning, Northern blot, mRNA induction assays The Journal of experimental medicine High 3260265
1989 CXCL8 (NAP-1) is chemotactic not only for neutrophils but also for T lymphocytes; intradermal injection caused dose-dependent accumulation of both neutrophils and lymphocytes in rats. In vitro chemotaxis assay, in vivo rat injection model Science (New York, N.Y.) High 2648569
1989 Two distinct CXCL8-binding polypeptides were identified on human neutrophils (~67 kDa and ~59 kDa) by chemical cross-linking; Scatchard analysis revealed ~20,000 high-affinity receptors per cell (Kd ~8×10⁻¹⁰ M). These receptors are distinct from IL-1α, TNF-α, fMLP, C5a, LTB4, and PAF receptors. ¹²⁵I-ligand binding, Scatchard analysis, chemical cross-linking, SDS-PAGE The Journal of experimental medicine High 2647892
1989 The CXCL8 gene (MDNCF/IL-8) consists of 4 exons and 3 introns. The 5'-flanking region contains potential binding sites for AP-1, AP-2, IRF-1, HNF-1, glucocorticoid response element, and heat shock element, providing a molecular basis for its transcriptional regulation by inflammatory stimuli and suppression by glucocorticoids. Genomic DNA cloning and sequencing, promoter analysis Journal of immunology (Baltimore, Md. : 1950) High 2663993
1990 The three-dimensional solution structure of the CXCL8 dimer was solved by NMR spectroscopy: two antiparallel α-helices (~24 Å long, separated by ~14 Å) lie on a six-stranded antiparallel β-sheet platform; the two C-terminal α-helices were proposed to form the receptor-binding site. NMR spectroscopy, hybrid distance geometry-dynamical simulated annealing (1880 distance restraints, 362 torsion angle restraints) Biochemistry High 2184886
1990 The CXCL8 gene maps to human chromosome 4q12–q21, co-localizing with platelet factor 4, MGSA, and IFN-γ-induced factor—all members of the platelet factor 4 gene superfamily—establishing CXCL8 as part of this gene cluster. Human-rodent somatic cell hybrid panel, in situ hybridization, RFLP analysis Human genetics High 1967588
1990 The CXCL8 coding region consists of 4 exons and 3 introns and is homogeneous across human cell types; the primary translation product carries an N-terminal AVLPR sequence (LUCT form) that is subsequently truncated to generate the mature form without this extension. PCR from genomic DNA of multiple cell types, sequencing Immunology letters Medium 2200751
1991 A cDNA encoding the CXCL8 receptor (IL-8RA/CXCR1) was cloned from human neutrophils; the protein is a G protein-coupled receptor (GPCR) 29% identical to fMLP and C5a receptors. Transfected mammalian cells bound IL-8 with high affinity and responded with transient calcium mobilization, establishing CXCR1 as a functional GPCR for CXCL8. cDNA expression cloning, radioligand binding, calcium mobilization assay in transfected cells Science (New York, N.Y.) High 1840701
1992 Macrophage-derived CXCL8 (IL-8) is potently angiogenic: recombinant IL-8 induced endothelial cell proliferation and chemotaxis in vitro and angiogenesis in the rat cornea in vivo. Anti-IL-8 antibodies blocked angiogenic activity of LPS-stimulated monocyte conditioned medium, and an IL-8 antisense oligonucleotide specifically blocked monocyte-induced angiogenic activity. Rat cornea implant angiogenesis assay, HUVEC proliferation and chemotaxis assay, neutralizing antibody blockade, antisense oligonucleotide Science (New York, N.Y.) High 1281554
1992 CXCL8 activates neutrophils inducing chemotaxis, exocytosis, and the respiratory burst; it is produced by phagocytes and mesenchymal cells in response to IL-1 or TNF stimulation. Neutrophil functional assays (chemotaxis, exocytosis, oxidative burst), cell stimulation FEBS letters High 1639201
1996 CXCL8 (IL-8) signals through two receptor subtypes with distinct selectivity: IL8RA (CXCR1) is highly selective for IL-8 (EC50 ~4 nM) with weak responses to other ELR+ CXC chemokines; IL8RB (CXCR2) is promiscuous, responding potently to GROα/β/γ, NAP-2, ENA-78, and IL-8 (EC50 1–11 nM). Receptor selectivity was determined by calcium flux in transfected HEK293 cells and competitive radioligand binding. Calcium flux assay in HEK293 cells transfected with CXCR1 or CXCR2, competitive radioligand binding with ¹²⁵I-labeled chemokines The Journal of biological chemistry High 8702798
1997 CXCL8 is transcytosed across venular endothelial cells from the abluminal to luminal surface, where it is presented on EC membrane projections to adherent leukocytes. The intact C-terminus of IL-8 (its glycosaminoglycan-binding/immobilization domain) is required for EC binding, transcytosis, and in vivo pro-emigratory activity. Electron microscopy of transcytosis, C-terminal deletion mutants, in vivo leukocyte emigration assay Cell High 9363947
2000 Neutrophil gelatinase B (MMP-9) cleaves full-length CXCL8(1-77) to generate CXCL8(7-77), which is 10–27-fold more potent in neutrophil activation (Ca²⁺ flux, gelatinase B secretion, chemotaxis), correlating with enhanced binding to neutrophils and increased CXCR1 signaling. This represents a positive feedback loop between MMP-9 and IL-8. In contrast, MMP-9 degrades CTAP-III, PF-4, and GRO-α but leaves RANTES and MCP-2 intact. In vitro MMP-9 cleavage, neutrophil Ca²⁺ signaling, degranulation assay, chemotaxis assay, receptor binding, CXCR1/CXCR2-transfected cell lines Blood High 11023497
2002 CXCL8 (IL-8) elicits angiogenic responses (stress fiber assembly, chemotaxis, ERK1/2 phosphorylation, tube formation) in human intestinal microvascular endothelial cells (HIMEC) specifically through CXCR2 (not CXCR1, which is absent on HIMEC). ERK1/2 and PI3K inhibitors abrogated these responses. RT-PCR, immunohistochemistry, flow cytometry, Western blot, neutralizing antibody, pharmacological inhibition, proliferation/chemotaxis assays, tube formation The Journal of biological chemistry High 12496258
2003 IL-8 directly promotes endothelial cell survival, proliferation, and MMP-2/MMP-9 production via CXCR1- and CXCR2-expressing endothelial cells. IL-8 inhibited apoptosis and enhanced Bcl-xL:Bcl-xS and Bcl-2:Bax ratios in HUVECs, and neutralizing anti-IL-8 antibody blocked capillary tube formation. CXCR1/CXCR2 expression analysis (RT-PCR, protein), proliferation assay, apoptosis assay, anti-apoptotic gene expression, MMP production, tube formation assay, neutralizing antibody Journal of immunology (Baltimore, Md. : 1950) High 12626597
2003 CXCL8 (IL-8) and GROα/CXCL1 induce chondrocyte hypertrophic differentiation (type X collagen, MMP-13, alkaline phosphatase expression, matrix calcification) via CXCR1 and CXCR2 through p38 MAPK signaling. Transglutaminase 2 (TG2) is essential for CXCL8-induced hypertrophy and calcification, acting downstream of p38. Primary human/bovine/mouse chondrocyte cultures, CXCR1/CXCR2 expression confirmation, p38 inhibition, TG2 knockout mouse chondrocytes, gene/activity assays Journal of immunology (Baltimore, Md. : 1950) High 14530367
2004 Oncogenic Ras signaling drives transcriptional upregulation of CXCL8 in tumor cells, and Ras-dependent CXCL8 secretion is required for tumor-associated inflammation and neovascularization in vivo. Ectopic CXCL8 expression rescued angiogenesis in Ras-signaling-impaired tumor xenografts. Tumor xenograft model, Ras signaling manipulation, CXCL8 reporter assays, in vivo angiogenesis assessment Cancer cell High 15542429
2004 CXCL8 (IL-8) acts as an autocrine growth factor for NSCLC lung cancer cells expressing both IL-8 and CXCR1/CXCR2; the mitogenic function is mediated predominantly by CXCR1 (not CXCR2), as shown by selective receptor-neutralizing antibodies. In SCLC cells (expressing receptors but not producing IL-8), exogenous IL-8 stimulated proliferation in a dose-dependent manner. Anti-IL-8 neutralizing antibody, anti-CXCR1 and anti-CXCR2 antibodies, MTT proliferation assay, PCNA analysis, cell cycle analysis British journal of cancer High 15545974
2005 2-Arylpropionic acid compounds (including repertaxin) are noncompetitive CXCL8 inhibitors that bind an allosteric site within the transmembrane (TM) region of CXCR1. The binding site was confirmed by alanine scanning mutagenesis and photoaffinity labeling of CXCR1. Molecular modeling, alanine scanning mutagenesis of CXCR1, photoaffinity labeling, PMN chemotaxis inhibition assay Journal of medicinal chemistry High 15974585
2006 Thrombin induces IL-8/CXCL8 expression in human lung epithelial cells (A549) through PAR1 and PAR4 receptors via a phosphoinositide-PLC/PKCα/c-Src/IKKαβ signaling cascade leading to NF-κB activation. PKCα, c-Src, and IKKαβ form a physical complex, and the CXCL8 NF-κB κB site is required for thrombin-induced transcription. Dominant-negative mutants, pharmacological inhibitors (U73122, Ro-32-0432, Bay 117082), κB-site luciferase reporter, Co-immunoprecipitation (PKCα/c-Src/IKKαβ complex), kinase activity assays, NF-κB EMSA Journal of immunology (Baltimore, Md. : 1950) High 16920985
2006 Murine CXCR1 is a functional receptor that binds and responds to human IL-8/CXCL8 and mouse/human GCP-2/CXCL6, but not to CXCR2-selective ligands (ENA-78, NAP-2, GRO-α/β/γ, CINC-1-3). Functional characterization included GTPγS exchange and chemotaxis of mCXCR1-transfected cells. Receptor transfection, radioligand binding, GTPγS exchange assay, chemotaxis assay The Journal of biological chemistry High 17197447
2008 Peptidylarginine deiminase (PAD) citrullinates CXCL8 at Arg5, generating CXCL8(1-77)Cit5. This modification: (i) reduces GAG affinity, (ii) reduces CXCR2-dependent Ca²⁺ signaling and ERK1/2 phosphorylation, (iii) confers resistance to thrombin/plasmin-dependent N-terminal processing to the more potent CXCL8(6-77) form, and (iv) abolishes neutrophil recruitment in vivo despite retained in vitro chemotactic activity. PAD citrullination in vitro, mass spectrometry identification of Cit5 on natural leukocyte CXCL8, GAG binding assay, Ca²⁺ signaling, ERK phosphorylation, thrombin/plasmin cleavage assay, in vivo peritoneal neutrophil recruitment, rabbit cornea angiogenesis assay The Journal of experimental medicine High 18710930
2009 CXCL8 promotes invasiveness and angiogenesis in pancreatic cancer through HUVEC proliferation/invasion and tube formation via paracrine signaling. Fibroblast-derived CXCL12 enhances CXCL8 production by PaCa cells, and PaCa-derived CXCL8 enhances CXCL12 production in fibroblasts, establishing a cooperative tumor-stromal loop. Co-culture systems, ELISA, Matrigel invasion assay, MTS proliferation assay, HUVEC tube formation assay, CXCR4/CXCR2 expression by RT-PCR International journal of cancer Medium 19035451
2009 Cell surface-bound IL-1α is an upstream regulator of senescence-associated IL-8/CXCL8 secretion in human fibroblasts. IL-1 receptor antagonist, neutralizing IL-1α antibodies, and IL-1α RNAi all suppressed senescence-associated IL-8 secretion. This pathway operates through IL-1R/IRAK1 → NF-κB/C/EBPβ → IL-8 transcription. RNAi knockdown, neutralizing antibodies, IL-1R antagonist, NF-κB DNA-binding assay, IRAK1 depletion, conditioned medium tumor invasion assay Proceedings of the National Academy of Sciences of the United States of America High 19805069
2009 MiR-146a/b are induced during cellular senescence and function as negative regulators of senescence-associated IL-6 and IL-8 secretion by downregulating IRAK1, a key IL-1R signaling component. Ectopic miR-146a/b expression in primary fibroblasts suppressed IL-6 and IL-8 secretion. miRNA profiling, ectopic miRNA expression, IRAK1 knockdown, ELISA for IL-6/IL-8, IL-1α neutralizing antibodies Aging High 20148189
2011 Glycosaminoglycan-mediated CXCL8 binding to endothelial cells induces downstream signaling (identified syndecan-4/SDC4 as a potential proteoglycan co-receptor) and changes in cytoskeletal organization proteins (Zyxin, Caldesmon), demonstrating a GAG-dependent signaling pathway distinct from CXCR1/CXCR2-mediated neutrophil signaling. Gene array, RT-PCR, flow cytometry (SDC4), enzymatic GAG depolymerization (heparinase III, chondroitinase ABC), proteomic analysis of endothelial protein expression changes International journal of molecular sciences Medium 29207576
2011 CXCL8 promotes endothelial cell migration through a heparan sulfate (HS)-dependent mechanism: removal of HS by heparinase III abolished CXCL8-induced wound healing, suppressed CXCL8-upregulated Cdc42, Rac1, and RhoA activity, and blocked actin polymerization, polarization, and stress fiber formation. Wound healing assay, heparinase III enzymatic HS removal, Rho GTPase activity assays (Cdc42, Rac1, RhoA), actin cytoskeleton imaging PeerJ Medium 26870616
2014 TSG-6 directly binds CXCL8 at its glycosaminoglycan-binding site (Kd ~25 nM), antagonizing CXCL8 association with heparin, impairing CXCL8 binding to cell-surface GAGs, blocking CXCL8 transcytosis across endothelial monolayers, and suppressing CXCL8-mediated neutrophil chemotaxis. TSG-6 is identified as the first soluble mammalian chemokine-binding protein. SPR binding (Kd measurement), heparin competition assay, transendothelial migration assay, cell-surface GAG binding assay, transwell chemotaxis assay Journal of immunology (Baltimore, Md. : 1950) High 24501198
2016 MiR-146a limits CXCL8/CXCL1-driven inflammation after renal ischemia-reperfusion injury via suppression of IRAK1. In miR-146a-/- mice, IRI caused more tubular injury, inflammatory infiltrates, and fibrosis; overexpression/knockdown of miR-146a in tubular cells inversely regulated IRAK1 and CXCL8/CXCL1. CXCL8/CXCL1 signaling inhibition rescued the miR-146a-/- phenotype. miR-146a knockout mice, unilateral IRI model, in vitro miRNA overexpression/knockdown, CXCL8 pathway inhibition rescue, IRAK1 expression analysis Journal of the American Society of Nephrology : JASN High 27444565
2017 ZO-1 (zonula occludens-1), when relocalized from tight junctions to the cytonuclear compartment, activates CXCL8/IL-8 transcription through a specific 173-bp promoter region containing a critical NF-κB (p65) site. ZO-1 overexpression promotes angiogenesis in ex vivo and in vivo assays, and NSCLC with cytonuclear ZO-1 was significantly more angiogenic. siRNA/cDNA transfection, luciferase reporter assay with promoter truncations and κB site mutation, p65 siRNA, IκBα/p65 phosphorylation analysis, ex vivo/in vivo angiogenesis assays FASEB journal : official publication of the Federation of American Societies for Experimental Biology High 28057697
2018 Citrullination of CXCL8 at Arg5 and N-terminal truncation to CXCL8(6-77) differentially modulate CXCR1 and CXCR2 internalization, Gαi-dependent signaling, and β-arrestin 1/2 recruitment. CXCL8(6-77) shows enhanced β-arrestin 2 recruitment to both CXCR1 and CXCR2; [Cit5]CXCL8 enhances β-arrestin 2 recruitment specifically to CXCR2. Neither modification acts as a biased agonist (no shift in G-protein vs. β-arrestin preference). Synthetic CXCL8 variants, neutrophil receptor internalization assays, Gαi signaling (HTRF), β-arrestin 1/2 recruitment assays (BRET) International journal of molecular sciences High 30486423
2019 Evasin-3 (a tick salivary protein) binds CXCL8 and disrupts both the GAG-binding site and the CXCR2 interaction surface of CXCL8, as revealed by solution NMR. Synthetic Evasin-3 variants (linear and cyclic peptides) bound CXCL8 with Kd ~13–27 nM and effectively inhibited CXCL8-induced PMN migration. Solution NMR structure of CXCL8–Evasin-3 complex, SPR binding assays, PMN chemotaxis inhibition assay, solid-phase peptide synthesis of truncated variants The Journal of biological chemistry High 31235521
2019 Notch1 activation in triple-negative breast cancer cells, driven by contact with MSCs or CAFs in a TNFα/IL-1β-inflammatory context, leads to NF-κB (p65) activation which in turn upregulates CXCL8 production in TNBC cells. Notch1 siRNA and DAPT (γ-secretase inhibitor) suppressed contact-dependent CXCL8 induction and TNBC migration/invasion. Notch1 siRNA, CRISPR/Cas9 p65 knockdown, CXCL8 siRNA, γ-secretase inhibitor (DAPT), co-culture contact vs. non-contact conditions, migration/invasion assays Frontiers in immunology High 31105691
2020 N-terminal truncation of CXCL8 to generate CXCL8(9-77) potentiates actin polymerization in neutrophils and significantly enhances in vivo neutrophil recruitment to the mouse peritoneal cavity compared to CXCL8(6-77), while Ca²⁺ signaling and in vitro chemotaxis potency are comparable between truncated forms. Actin polymerization assay, Ca²⁺ signaling, in vitro chemotaxis, in vivo peritoneal recruitment model, neutrophil surface marker assays (CD62L, CD11a/b, CD15), degranulation assay, phagocytosis assay Journal of leukocyte biology High 32272490
2022 Thrombin activates a DCLK1/RhoA/YAP signaling cascade in lung epithelial cells to induce CXCL8 expression. DCLK1 (activated via ERK) activates RhoA and promotes YAP dephosphorylation at Ser127 and nuclear translocation; nuclear YAP forms a complex with p65 (NF-κB) and both are recruited to the NF-κB site on the CXCL8 promoter. DCLK1 siRNA blocked RhoA, YAP activation, κB-luciferase activity, and p65/YAP promoter binding. siRNA (DCLK1, YAP), pharmacological inhibitors (DCLK1, ERK), ChIP assay (YAP and p65 at IL-8 promoter), luciferase reporter, Western blot (pSer127-YAP), immunofluorescence (YAP localization), ELISA, in vivo asthma model (OVA-induced) Journal of biomedical science High 36369000
2023 CXCL8 maintains the mesenchymal state of glioblastoma stem cells (GSCs) via cell-intrinsic PI3K/AKT and NF-κB signaling, and drives M2-like TAM polarization through a cell-extrinsic CXCR2-JAK2/STAT3 axis. Combined genetic/pharmacological inhibition of these dual pathways suppressed GBM tumor growth and prolonged survival in orthotopic xenograft models. Patient-derived GSC cultures, xenograft model, multi-omics RNA-seq, genetic inhibition (CXCL8/CXCR2 knockdown), small molecule inhibitors, TAM polarization assays, PI3K/AKT and JAK2/STAT3 pathway analysis Clinical cancer research : an official journal of the American Association for Cancer Research High 37439870
2023 CXCL8/CXCR2 signaling mediates bone marrow fibrosis in myelofibrosis: hematopoietic stem/progenitor cells from MF patients display enriched CXCL8/CXCR2 signatures. Genetic deletion of Cxcr2 in a murine MF model abrogated fibrosis and extended survival; pharmacological CXCR1/2 inhibition attenuated fibrosis and synergized with JAK inhibitor therapy. Single-cell transcriptomics, cytokine secretion studies, Cxcr2 genetic knockout in adoptive transfer model, pharmacological CXCR1/2 inhibition, in vitro HSC proliferation assay with CXCL8 Blood High 36800567

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1992 Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science (New York, N.Y.) 1853 1281554
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
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