CXCL5 (chemokine (C-X-C motif) ligand 5)

2013-05-01   Anna A Bulysheva , W Andrew Yeudall 

VCU Philips Institute of Oral, Craniofacial Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA




Atlas Image
Solid blue boxes - coding regions; patterned boxes - non-coding regions; single lines - intervening (intronic) sequences; start / stop codons and direction of transcription are indicated.


The CXCL5 gene is located on human chromosome 4 at 4q13.3, starting at position 74861359 and ending at position 74864496 on the reverse strand. It consists of 4 exons.


The transcript consists of 2538bp. The coding sequence begins at residue 119 and ends at residue 463. The mRNA is polyadenylated and is translated to produce a 114 residue polypeptide.


Atlas Image
Schematic representation of human CXCL5. C-X-C motif is indicated in red, together with predicted intrachain disulphide bridges; E-L-R motif is indicated in blue.


The full length polypeptide consists of 114 amino acids. The N-terminal 36 amino acids are removed to generate the mature molecule 78 amino acids in length. An E-L-R (Glu-Leu-Arg) motif, important for receptor binding, is found immediately N-terminal to the C-X-C motif (Cys-Val-Cys). The E-L-R motif is found in pro-angiogenic chemokines (Belperio et al., 2000), while the presence of the C-X-C motif places this protein into the CXC-chemokine family. CXCL5 has homology to CXCL8 (Walz et al., 1991).


Ubiquitous in adult.




Chemotaxis, neutrophil activation, angiogenesis. Human CXCL5 is a substrate for several proteases (Van den Steen et al., 2003; Dean et al., 2008; Starr et al., 2012). These include matrix metalloprotease MMP-1, MMP-9, MMP-12, and MMP-25 (MT6-MMP), which cleave the N-terminal region of the mature (78aa) polypeptide. MMP-12 has been reported to inactivate CXCL5, as it results in cleavage within the ELR motif, as well as between residues 5 and 6. MMP-25 is also thought to activate CXCL5 by removing the N-terminal 7 amino acids from the mature polypeptide, resulting in a 71 amino acid product (8-78). MMP-9 digests CXCL5 at multiple sites: early proteolysis involves the N-terminal region and is thought to potentiate CXCL5 activity, whereas later proteolysis (upon extended incubation with the protease) results in CXCL5 inactivation.


IL-8. Conservation of this gene is observed in chimpanzee, dog and cow.

Implicated in

Entity name
Cancer, pulmonary fibrosis, inflammatory diseases and endometriosis.
CXCL5 is reportedly overexpressed in a number of human tumors such as head and neck squamous cell carcinoma, gastric, pancreatic, colorectal, prostate and lung cancer as well as in lung tissue of patients with pulmonary fibrosis. CXCL5 was found to be upregulated in many types of inflammatory conditions. It plays a significant role in inflammation that occurs in diseases such as acute coronary syndrome, allergy, rheumatoid arthritis, inflammatory bowel disease, pulmonary sarcoidosis, pancreatitis and endometriosis.
Abnormal expression of CXCL5 has been correlated with increased tumor cell motility and proliferation in vitro and increased tumorigenicity in vivo. It is also associated with worse clinical prognosis in several cancer types.
Entity name
Head and neck squamous cell carcinoma
It has been reported that metastatic head and neck cancer cells express comparatively high levels of CXCL5 relative to primary tumor cells, as measured by microarray and confirmed by quantitative real-time PCR and analysis of conditioned medium (Miyazaki et al., 2006). Biological consequences of CXCL5 overexpression have been investigated in terms of tumor cell proliferation and motility, both of which are reduced if CXCL5 expression is inhibited. In vivo growth of xenografted tumor cells was abrogated when CXCL5 expression was repressed by small hairpin RNA.
Entity name
Gastric cancer
Overexpression of CXCL5 has been found to correlate with late stage gastric cancer and high N stage, suggesting a role for CXCL5 in progression of gastric cancer and nodal metastasis (Park et al., 2007). This was revealed by immunostaining of gastric tumors for CXCL5, as well as enzyme-linked immunosorbent assay (ELISA) measurement of serum CXCL5 levels.
Entity name
Colorectal cancer
Low expression of CXCL5 in a rat model of colorectal cancer has been reported to increase the tumorigenic potential of cells that would otherwise form a less aggressive type of colon cancer (Speetjens et al., 2008). It has also been observed that human patients with low CXCL5 levels in their colorectal tumors had a poorer prognosis than those with higher expression of CXCL5.
Entity name
Pancreatic cancer
CXCL5 is secreted by pancreatic cancer cell lines, and antibody-mediated blockade of the CXCR2 receptor inhibits neovascularization in corneal angiogenesis assays (Wente et al., 2006). CXCL5 is also overexpressed in pancreatic cancer specimens, and is linked to poor patient survival (Frick et al., 2008). Blocking CXCR2 with an antibody, or inhibiting CXCL5 expression with siRNA, inhibits tumor xenograft formation. CXCL5 activates signaling through AKT-, ERK- and STAT-dependent pathways in pancreatic cancer cells (Li et al., 2011).
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Prostate cancer
Androgen-independent prostate cancers tend to overexpress CXCL5. It has been reported that CXCL5 overexpression leads to increased cell migration and epithelial-to-mesenchymal transition (Kuo et al., 2011).
Entity name
Non-small cell lung cancer
CXCL5 was found to play a role in development of non-small cell lung cancer by enhancing tumor angiogenesis (Arenberg et al., 1998). High expression of CXCL5 was correlated with vascularity of tumors. Passive immunity against CXCL5 resulted in a reduction of tumor growth, vascularity and metastases in vivo, although there was no effect of passive immunity on tumor cell proliferation.
Entity name
Pulmonary fibrosis
Analysis of bronchoalveolar lavage (BAL) fluid and lung tissue from patients with idiopathic pulmonary fibrosis revealed elevated levels of the angiogenic chemokines CXCL5 and CXCL8, together with a relative decrease of angiostatic factors, correlating with increased fibrosis of lung tissue (Streiter et al., 2007).
Entity name
Acute coronary syndrome (ACS)
Examination of CXCL5 in inflammation associated with acute coronary syndrome indicated that a polymorphism in CXCL5 (156G>C; rs352046) was linked to a 2.7-fold rise in 3-year mortality (all causes; C/C genotype only). Mortality was reduced in G/G genotype individuals by the use of statins. Treatment of human umbilical vein endothelial cells (HUVECs) with atorvastatin in vitro reduced the levels of IL-1β-induced CXCL5 in a dose-dependent manner (Zineh et al., 2008).
Entity name
Activated mast cells have been shown to increase CXCL5 production significantly compared to the level of CXCL5 in resting cells. Supernatants from sonicated MC-9 mast cells elicited a significant influx of neutrophils when injected intratracheally in mice. When the same supernatants were preincubated with CXCL5-specific antibodies, neutrophil influx was dramatically reduced, implicating CXCL5 produced by activated mast cells as a critical chemoattractant for neutrophils (Lukacs et al., 1998).
Entity name
Rheumatoid arthritis (RA)
CXCL5 is reported to be significantly elevated in synovial fluid of patients with rheumatoid arthritis compared to patients with other forms of arthritis (Koch et al., 1994). Studies of rat adjuvant-induced arthritis (AIA), as a model for RA, showed elevated CXCL5 levels in serum with progressive development of arthritis compared to control animals. Joint homogenates also had increased levels of CXCL5 and this correlated with disease progression. Anti-CXCL5 antibody treatments prior to the onset of AIA decreased the severity of the disease (Halloran et al., 1999). The results indicate that CXCL5 plays an important role in the onset and progression of RA.
Entity name
Inflammatory bowel disease
Immunohistochemical studies of colonic epithelial cells in normal subjects and patients with inflammatory bowel disease showed that CXCL5 is expressed predominantly by crypt epithelial cells (Keates et al., 1997). CXCL5 production is significantly higher in patients with ulcerative colitis, with less intense expression in Crohns disease patients.
Entity name
Pulmonary sarcoidosis
Increased levels of CXCL5 were found in the serum and BAL fluid of patients with pulmonary sarcoidosis compared to normal subjects, as judged by ELISA. BAL levels of CXCL5 were elevated in stage III sarcoidosis (Sujiyama et al., 2006).
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Patients with severe acute pancreatitis had significantly higher serum levels of CXCL5 compared to individuals with mild acute pancreatitis (Shokuhi et al., 2002). Samples from patients with chronic pancreatitis also showed higher expression of CXCL5 than normal pancreatic tissues, predominantly in centroacinar ducts of pancreatic lobuli (Saurer et al., 2000). These findings suggest a role for CXCL5 in development and maintenance of both acute and chronic pancreatitis.
Entity name
CXCL5 has also been implicated in the pathogenesis of endometriosis, with elevated levels of CXCL5 found in peritoneal fluid of patients with endometriosis compared to control subjects (Mueller et al., 2003). Further studies showed that glandular cells, stromal fibroblasts and peritoneal macrophages were primarily responsible for CXCL5 production in patients with endometriosis. Elevated levels of CXCL5 have also been found in the follicular fluid of patients with endometriosis compared to controls (Wunder et al., 2006). Together, these studies implicate CXCL5 in the pathogenesis of endometriosis.


Pubmed IDLast YearTitleAuthors
96910821998Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer.Arenberg DA et al
109144832000CXC chemokines in angiogenesis.Belperio JA et al
186603812008Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx.Dean RA et al
187659532008Enhanced ENA-78 and IL-8 expression in patients with malignant pancreatic diseases.Frick VO et al
103582041999The role of an epithelial neutrophil-activating peptide-78-like protein in rat adjuvant-induced arthritis.Halloran MM et al
92525121997Enterocytes are the primary source of the chemokine ENA-78 in normal colon and ulcerative colitis.Keates S et al
80833421994Epithelial neutrophil activating peptide-78: a novel chemotactic cytokine for neutrophils in arthritis.Koch AE et al
209453842011CXCL5/ENA78 increased cell migration and epithelial-to-mesenchymal transition of hormone-independent prostate cancer by early growth response-1/snail signaling pathway.Kuo PL et al
213563842011Overexpression of CXCL5 is associated with poor survival in patients with pancreatic cancer.Li A et al
96206681998Mast cells produce ENA-78, which can function as a potent neutrophil chemoattractant during allergic airway inflammation.Lukacs NW et al
166187522006Down-regulation of CXCL5 inhibits squamous carcinogenesis.Miyazaki H et al
126204962003Epithelial neutrophil-activating peptide 78 concentrations are elevated in the peritoneal fluid of women with endometriosis.Mueller MD et al
174792872007CXCL5 overexpression is associated with late stage gastric cancer.Park JY et al
106484642000Differential expression of chemokines in normal pancreas and in chronic pancreatitis.Saurer L et al
119725452002Levels of the chemokines growth-related oncogene alpha and epithelial neutrophil-activating protein 78 are raised in patients with severe acute pancreatitis.Shokuhi S et al
184138162008Disrupted expression of CXCL5 in colorectal cancer is associated with rapid tumor formation in rats and poor prognosis in patients.Speetjens FM et al
223671942012Biochemical characterization and N-terminomics analysis of leukolysin, the membrane-type 6 matrix metalloprotease (MMP25): chemokine and vimentin cleavages enhance cell migration and macrophage phagocytic activities.Starr AE et al
173328822007The role of CXC chemokines in pulmonary fibrosis.Strieter RM et al
170522982006Elevated levels of interferon gamma-inducible protein-10 and epithelial neutrophil-activating peptide-78 in patients with pulmonary sarcoidosis.Sugiyama K et al
129502572003Gelatinase B/MMP-9 and neutrophil collagenase/MMP-8 process the chemokines human GCP-2/CXCL6, ENA-78/CXCL5 and mouse GCP-2/LIX and modulate their physiological activities.Van Den Steen PE et al
17445771991Structure and neutrophil-activating properties of a novel inflammatory peptide (ENA-78) with homology to interleukin 8.Walz A et al
164584212006Blockade of the chemokine receptor CXCR2 inhibits pancreatic cancer cell-induced angiogenesis.Wente MN et al
165531832006Increased ENA-78 in the follicular fluid of patients with endometriosis.Wunder DM et al
187696202008Epithelial neutrophil-activating peptide (ENA-78), acute coronary syndrome prognosis, and modulatory effect of statins.Zineh I et al

Other Information

Locus ID:

NCBI: 6374
MIM: 600324
HGNC: 10642
Ensembl: ENSG00000163735


dbSNP: 6374
ClinVar: 6374
TCGA: ENSG00000163735


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Cytokine-cytokine receptor interactionKEGGhsa04060
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
Rheumatoid arthritisKEGGko05323
Rheumatoid arthritisKEGGhsa05323
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Signal TransductionREACTOMER-HSA-162582
Signaling by GPCRREACTOMER-HSA-372790
GPCR ligand bindingREACTOMER-HSA-500792
Class A/1 (Rhodopsin-like receptors)REACTOMER-HSA-373076
Peptide ligand-binding receptorsREACTOMER-HSA-375276
Chemokine receptors bind chemokinesREACTOMER-HSA-380108
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (i) signalling eventsREACTOMER-HSA-418594
IL-17 signaling pathwayKEGGko04657
IL-17 signaling pathwayKEGGhsa04657

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA133950441hmg coa reductase inhibitorsChemicalClinicalAnnotationassociatedPD18769620
PA165108401Acute coronary syndromeDiseaseClinicalAnnotationassociatedPD18769620


Pubmed IDYearTitleCitations
177034122007Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes.100
227116852012Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma.71
193567152009CXC ligand 5 is an adipose-tissue derived factor that links obesity to insulin resistance.65
183200692008CXCL5 promotes prostate cancer progression.56
254628582015CXCR2/CXCL5 axis contributes to epithelial-mesenchymal transition of HCC cells through activating PI3K/Akt/GSK-3β/Snail signaling.49
221972192012CXCL5, a promoter of cell proliferation, migration and invasion, is a novel serum prognostic marker in patients with colorectal cancer.41
217341762011CXCL5 mediates UVB irradiation-induced pain.36
221256412011Tumour tissue microenvironment can inhibit dendritic cell maturation in colorectal cancer.36
283561112017Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3β/β-catenin pathways.36
260587292015CXCL5/CXCR2 axis promotes bladder cancer cell migration and invasion by activating PI3K/AKT-induced upregulation of MMP2/MMP9.32


Anna A Bulysheva ; W Andrew Yeudall

CXCL5 (chemokine (C-X-C motif) ligand 5)

Atlas Genet Cytogenet Oncol Haematol. 2013-05-01

Online version: