Disease relevance of CXCL5

• Chemotactic activity of CXCL5 in cerebrospinal fluid of children with bacterial meningitis [1].
• CXCL5 was not detectable in patients with aseptic meningitis or control subjects [1].
• By in situ hybridization and immunofluorescence staining, ENA-78 has been recognized as a major CXC chemokine expressed in epithelial cells of the intestinal mucosa of patients with Crohn's disease, ulcerative colitis, and acute appendicitis [2].
• A high expression of ENA-78 and interleukin-8 (IL-8) was also observed in the exocrine tissue of patients with chronic pancreatitis (CP) [2].
• ENA-78 does not seem to play a pivotal role in tonsillitis in vivo [3].
• We found that low expression of CXCL5 was significantly associated with poor prognosis for colorectal cancer patients [4].

High impact information on CXCL5

• Structure and neutrophil-activating properties of a novel inflammatory peptide (ENA-78) with homology to interleukin 8 [5].
• Like NAP-2 and GRO alpha, ENA-78 stimulates neutrophils, inducing chemotaxis, a rise in intracellular free calcium and exocytosis [5].
• A new neutrophil-activating peptide, termed ENA-78, was identified in the conditioned media of stimulated human type II epithelial cell line A549 [5].
• In a SCID mouse model of human NSCLC tumorigenesis, expression of ENA-78 in developing tumors correlated with tumor growth in two different NSCLC cell lines [6].
• Furthermore, passive immunization of NSCLC tumor-bearing mice with neutralizing anti-ENA-78 antibodies reduced tumor growth, tumor vascularity, and spontaneous metastases, while having no effect on the proliferation of NSCLC cells either in vitro or in vivo [6].

Chemical compound and disease context of CXCL5

• OBJECTIVE: To assess the release of epithelial neutrophil-activating peptide-78 (ENA-78) into peritoneal fluid in women with and without endometriosis [7].
• CONCLUSIONS: The endometrial production of ENA-78 is altered in progestin-only contraceptive users experiencing breakthrough bleeding and is regulated by MPA and TNF-alpha in ESCs [8].

Biological context of CXCL5

• By measuring calcium flux in human embryonic kidney 293 cells transfected with plasmids encoding IL8RA or IL8RB, we have now defined receptor selectivity for GRObeta, GROgamma, and ENA-78 [9].
• Interleukin-8 (IL-8) and closely related Glu-Leu-Arg (ELR) containing CXC chemokines, including growth-related oncogene (GRO)alpha, GRObeta, GROgamma, and epithelial cell-derived neutrophil-activating peptide-78 (ENA-78), are potent neutrophil chemotactic and activating peptides, which are proposed to be major mediators of inflammation [10].
• The human ENA-78 gene was mapped to chromosome 4q13-q21, the same locus as several other inflammatory cytokine genes [11].
• Despite 85% identity of the first 270 nucleotides 5' of the transcription start sites, GCP-2 and ENA-78 show cell-specific differences in regulation [12].
• Infected endometrial cells demonstrated up-regulation of ENA-78 and GCP-2 chemokine mRNA [13].

Anatomical context of CXCL5

• These data confirm that sIL-6R-mediated signaling primarily limits neutrophil influx; however, induction of CXCL5 and CXCL6 may regulate other neutrophil responses [14].
• Immunocytochemistry detected CXCL5 in eosinophils and the peptide was localized in the specific granules by immunoelectron microscopy [15].
• During bacterial meningitis, CXCL5 is elevated in CSF, where it is involved in the recruitment of neutrophils to the central nervous system [1].
• RECENT FINDINGS: Of particular interest are reports describing novel interactions between chemokines and both eosinophils and mast cells, including a role for CXCL5 (epithelial cell-derived neutrophil-activating peptide-78) and intracellular CCR3 [16].
• ENA-78 protein levels are strongly elevated in synovial fluid and blood of patients with rheumatoid arthritis [2].

Associations of CXCL5 with chemical compounds

• Preincubation with IL-8, MGSA, or ENA-78 enhanced the ability of neutrophils to generate O-2 following stimulation with the bacterial peptide formyl-Met-Leu-Phe [17].
• Isolation of the CXC chemokines ENA-78, GRO alpha and GRO gamma from tumor cells and leukocytes reveals NH2-terminal heterogeneity. Functional comparison of different natural isoforms [18].
• RA synovial fluid mononuclear cells spontaneously produced ENA-78, which was augmented in the presence of lipopolysaccharide [19].
• (3) The oxidized low density lipoprotein-induced release of ENA-78 from peripheral blood mononuclear cells from control subjects was significantly reduced when cells were incubated in the presence of folic acid [20].
• Data showed the following: (1) Compared with control subjects, hyperhomocysteinemic subjects had elevated plasma levels of the CXC chemokines, epithelial neutrophil-activating peptide (ENA)-78 (P<0.05), and growth-regulated oncogene (GRO)alpha (P=0.088), and homocysteine was significantly correlated with ENA-78 and GROalpha [20].

Regulatory relationships of CXCL5

• Addition of TNF-alpha neutralizing antibodies during prolonged incubation significantly inhibited CXCL5 production, demonstrating involvement of auto- and paracrine effects from TNF-alpha produced by eosinophils themselves [15].
• In addition, ENA-78 appears to activate neutrophils through the IL-8 receptor [21].
• The results suggest that GCP-2 gene expression is more tightly regulated in diseased or injured corneal tissue than is ENA-78 gene expression [22].
• Epithelial-neutrophil activating peptide-78 (ENA-78) induces neutrophil migration, an early response to viral infection [23].
• This was demonstrated in experiments in which we found that ENA-78 induces inside-out signaling of beta2 integrins on the PMN surface, as does IL-8 [24].

Other interactions of CXCL5

• RANTES, MCP-1, ENA-78, and GROalpha produced in culture supernatants were measured by enzyme-linked immunosorbent assay [25].
• EGCG at 50 microM caused a complete block of IL-1beta-induced production of RANTES, ENA-78, and GROalpha, and reduced production of MCP-1 by 48% (P < 0.05) [25].
• A protein concentration of GCP-2 was induced in PA and RT, whereas ENA-78 remained the same in all entities [26].
• The order of neutrophil chemotactic potency of these CXC chemokines was GRO alpha > GRO gamma > ENA-78 both for intact and truncated forms [18].
• Chemokines CXCL10 and CXCL11 were upregulated, whereas CXCL5 was downregulated [27].

Analytical, diagnostic and therapeutic context of CXCL5

• METHODS AND RESULTS: In eosinophil lysates, 12 +/- 2 pg (mean +/- SEM) of CXCL5 was detected per 106 cells by enzyme-linked immunosorbent assay (ELISA) [15].
• Weak constitutive expression of CXCL5, as well as the related CXC chemokine IL-8/CXCL8, could be detected in freshly isolated eosinophils by RT-PCR [15].
• No significant differences in serum CXCL5 levels were found between the stroke patients and the control group [28].
• If neutrophils were treated with fMLP, IL-8, C5a, ENA-78, or GRO-alpha just before perfusion over this HUVEC, transmigration, but not adhesion, was abolished [29].
• HUS patients requiring peritoneal dialysis showed 6-fold increased G-CSF (p < 0.001) and 5-fold decreased ENA-78 (p < 0.001) levels [30].

References