Disease relevance of CXCL6

• Production and upregulation of granulocyte chemotactic protein-2/CXCL6 by IL-1beta and hypoxia in small cell lung cancer [1].
• The patterns of producer cell types, inducers and kinetics and the quantities of GCP-2 produced, suggest a unique role for GCP-2 in physiologic and pathologic processes [2].
• This study provides the first evidence that GCP-2 protein is, compared with IL-8, weakly produced by some sarcoma, but less by carcinoma cells, and is tightly regulated in normal mesenchymal cells [2].
• IL-1beta was the predominant GCP-2 inducer in fibroblasts, chondrocytes, and endothelial cells, whereas IL-8 was equally well up-regulated in these cells by TNF-alpha, measles virus, or double-stranded RNA (dsRNA) [2].
• IL-8 and GCP-2 are expressed in an acute type of tonsillitis whereas GRO-alpha was frequently detectable both in chronically and acutely inflamed tonsils [3].

High impact information on CXCL6

• To conclude, our findings shed light on the interrelationships between GCP-2 and other ELR(+)-CXC chemokines, and determine the mechanisms involved in the regulation of GCP-2-induced internalization and recycling of CXCR2 [4].
• Three of the 10 transcripts encoded CXC chemokines (CXCL1, CXCL2, and CXCL6) [5].
• These data confirm that sIL-6R-mediated signaling primarily limits neutrophil influx; however, induction of CXCL5 and CXCL6 may regulate other neutrophil responses [6].
• Neutralization experiments indicated that chemotaxis was mainly mediated by CXCL8, but not by granulocyte chemotactic protein-2/CXCL6, epithelial cell-derived neutrophil attractant-78/CXCL5, or growth-related oncogene-alpha,beta,gamma/CXCL1,2,3 [7].
• Both concentrations are similar to the effective concentrations of IL-8 and less than the effective concentrations of other neutrophil chemoattractants such as neutrophil-activating peptide-78, granulocyte chemotactic protein-2, leukotriene B(4), and FMLP [8].

Chemical compound and disease context of CXCL6

• By means of PCR on cloned cDNA of osteosarcoma cells induced by interleukin-1 beta and fibroblasts induced by lipopolysaccharide plus dsRNA, the complete coding domain of GCP-2 was isolated [9].

Biological context of CXCL6

• The exact amino acid sequence of synthetic GCP-2 was confirmed by Edman degradation [10].
• In order to understand the role of this new protein in inflammatory reactions, we cloned GCP-2 DNA sequences to generate recombinant protein and specific DNA probes and primers [9].
• In addition, GCP-2 and ENA-78 expression seem to be differentially regulated in that phorbol ester and lipopolysaccharide have opposing effects on their mRNA induction in diploid fibroblasts and epithelial cells, respectively [9].
• 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 [11].
• The results suggest that GCP-2 gene expression is more tightly regulated in diseased or injured corneal tissue than is ENA-78 gene expression [12].

Anatomical context of CXCL6

• In contrast, stimulated endothelial cell cultures produced more IL-8 than GCP-2 [13].
• In contrast, lipopolysaccharide (LPS) was a relatively better stimulus for GCP-2 versus IL-8 in fibroblasts [2].
• However, lung macrophages and blood monocyte-derived macrophages produced GCP-2 in response to LPS [2].
• GCP-2 staining correlated with leukocyte infiltration into the tumor and with the expression of the matrix metalloproteinase-9 (MMP-9/gelatinase B) [14].
• Synthetic GCP-2 was an equally active (minimal effective concentration of 1-3 nM) chemoattractant for neutrophilic granulocytes as was natural 75-residue GCP-2 [10].

Associations of CXCL6 with chemical compounds

• A variant of GCP-2 in which the basic residue, Arg20, was replaced by a glycine was synthesized [15].
• When compared with epithelial-cell-derived neutrophil-activating peptide-78 (ENA-78) mRNA, the GCP-2 mRNA levels were higher in all cell lines tested [9].

Physical interactions of CXCL6

• Only IL-8 and GCP-2 bind CXCR-1 with high affinity [16].

Regulatory relationships of CXCL6

• IFN-gamma down-regulated the GCP-2 production in fibroblasts induced by IL-1beta, TNF-alpha, LPS, or dsRNA [2].
• Human GCP-2 induced [Ca2+]i increases and chemotactic responses in both CXCR1- and CXCR2-transfected cells [17].
• In addition, expression of the proliferation marker PCNA was upregulated by exogenous GCP-2 in two low-GCP-2-producing cell lines [1].

Other interactions of CXCL6

• This derivative was ineffective on CXCR1, but was as active as wild-type GCP-2 in CXCR2-expressing cells [15].
• Rabbit neutrophil chemotactic protein (NCP) activates both CXCR1 and CXCR2 and is the functional homologue for human CXCL6 [18].
• The differential receptor usage of the structurally related ELR+ CXC chemokines GCP-2 and ENA-78 is indicative of a different role in inflammatory reactions [19].
• In contrast with its weak proliferative effect on endothelial cells, GCP-2 synergized with MCP-1 in neutrophil chemotaxis [14].
• GCP-2 may serve as a substitute chemokine in certain inflammatory conditions as its quantity of mRNA and protein was higher in RT and PA than in HT [20].

Analytical, diagnostic and therapeutic context of CXCL6

• The expression of GCP-2 was confirmed in vivo by immunohistochemistry [2].
• Quantitatively, secretion of GCP-2 always remained inferior to that of IL-8, despite the fact that the ELISA recognized all posttranslationally modified GCP-2 isoforms [2].
• Intradermal injection of synthetic GCP-2 resulted in a dose-dependent neutrophil accumulation and plasma extravasation in rabbit skin [10].
• After disulfide bridge formation and purification, monomeric GCP-2 was recovered as a 6-kDa protein; the pure synthetic protein showed a molecular mass of 8076 Da as determined by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) [10].
• Furthermore, the complete coding domain of human GCP-2 was disclosed by means of RT-PCR [17].

References