Disease relevance of CXCL1

• Our previous studies have revealed that the CXC chemokine, CXCL1, is overexpressed in human malignant melanoma cells and is linked to transformation of immortalized murine melanocytes [1].
• These included growth regulated oncogene alpha (GROalpha/GRO1/CXCL1), another neutrophil chemoattractant implicated in tumor angiogenesis and metastasis [2].
• Because neutrophils constitute the majority of the cellular infiltrate in early brain abscess development, subsequent analysis focused on MIP-2 and KC/CXCL1, two neutrophil-attracting CXC chemokines [3].
• Role for CXCR2 and CXCL1 on glia in multiple sclerosis [4].
• CSF from patients with bacterial meningitis exerted chemotactic activity towards neutrophils, which was partially inhibited by neutralizing antibodies against CXCL5 and CXCL8, but not CXCL1 [5].

Psychiatry related information on CXCL1

• Association study of the chemokine, CXC motif, ligand 1 (CXCL1) gene with sporadic Alzheimer's disease in a Japanese population [6].

High impact information on CXCL1

• Third, both MGSA and IL-8 blocked the binding of the parasite ligand and the invasion of human erythrocytes by P. knowlesi, suggesting the possibility of receptor blockade for anti-malarial therapy [7].
• Like NAP-2 and GRO alpha, ENA-78 stimulates neutrophils, inducing chemotaxis, a rise in intracellular free calcium and exocytosis [8].
• NAP-3 (MGSA/gro) appears to represent the first member of the novel supergene family of beta-thromboglobulin-like host defense cytokines, which expresses both mitogenic as well as proinflammatory properties at the nanogram level [9].
• Determination of neutrophil chemotactic activity of NAP-3 revealed a typical bell-shaped dose-response curve (ED50 = 2 ng/ml) with no significant neutrophil chemotactic activity at doses greater than 200 ng/ml [9].
• The sequence is identical to that found for the 13-kD moiety of melanoma growth stimulating activity (MGSA) and the product of the oncogene gro [9].

Chemical compound and disease context of CXCL1

• Alanine scanning mutagenesis of the charged amino acids of melanoma growth stimulating activity (MGSA) was used to identify specific residues that are involved in binding to the human erythrocyte Duffy antigen/chemokine receptor (DARC) and to the type B interleukin-8 receptor (IL-8RB) on neutrophils [10].
• Oleate and palmitate also induced expression of chemokines (MCP-1 and GRO1 oncogene) and genes of the acute phase response (serum amyloid A3) [11].
• Functional analyses with neutralizing antibodies limited bromodeoxyuridine incorporation in vitro by oligodendroglioma tumor cells, demonstrating a requirement for the GRO1-PDGF pathway in the proliferation of these cells [12].
• No correlation between concentration of GRO-alpha, stage of endometriosis, duration of infertility or sex steroid hormone levels was found [13].
• In summary, our findings provide evidence that human breast cancer cells express and secrete GRO and implicate this cytokine as an essential mediator of the antiinvasive properties of Syk tyrosine kinase [14].

Biological context of CXCL1

• Gene expression profiling revealed that the 3 oncogenes activate a common transcriptional program in thyroid cells that includes upregulation of the CXCL1 and CXCL10 chemokines, which in turn stimulate proliferation and invasion [15].
• PAK1 kinase is required for CXCL1-induced chemotaxis [16].
• To better understand the molecular mechanisms by which CXCL1 induces CXCR2-mediated chemotaxis, the signal transduction components involved in CXCL1-induced chemotaxis were examined [16].
• These data demonstrate that the constitutive expression of CXCL1 and its receptor CXCR2 is associated with metastatic potential and modulates colon cancer cell proliferation and an invasive phenotype [17].
• Neutralizing antibody to CXCL1 in combination with antibody to CXCR2 inhibited highly metastatic KM12L4 (high CXCL1 expressor) cell proliferation [17].

Anatomical context of CXCL1

• The chemokines, CXC ligand 1 (CXCL1) and CXCL8, but not CXCL5, are highly expressed in most of the melanoma cell lines, suggesting that the constitutive production of chemokines is highly correlated to endogenous NF-kappaB activity [18].
• In addition, the melanoma growth and migration stimulatory chemokines CXCL1 and CXCL2 were significantly up-regulated in the cocultured fibroblasts [19].
• IL-8/CXCL8 and growth-related oncogene alpha/CXCL1 induce chondrocyte hypertrophic differentiation [20].
• We identified two chemokines: Growth-Regulated Oncogene-alpha (Gro-alpha; CXCL1) and Regulated on Activation Normal T Cell-Expressed and Secreted (RANTES; CCL5), to be secreted by several human tumor cell lines [21].
• At the functional level, following stimulation with the proinflammatory cytokine, interleukin-1beta (IL-1beta), we found high-level synthesis of CXCL1 by human fetal astrocytes in vitro [4].

Associations of CXCL1 with chemical compounds

• Cell surface heparan sulfate participates in CXCL1-induced signaling [22].
• Lipopolysaccharide-stimulated human monocytes secrete, apart from neutrophil-activating peptide 1/interleukin 8, a second neutrophil-activating protein. NH2-terminal amino acid sequence identity with melanoma growth stimulatory activity [9].
• The melanoma growth stimulatory activity receptor consists of two proteins. Ligand binding results in enhanced tyrosine phosphorylation [23].
• The CXC chemokines growth-regulated oncogene (GRO) alpha, GRObeta, GROgamma, neutrophil-activating peptide-2, and epithelial cell-derived neutrophil-activating peptide-78 are potent agonists for the type B, but not the type A, human interleukin-8 receptor [24].
• Zn(II) in activating concentrations (100 muM) acted as an allosteric enhancer as it increased the B(max) (7.1-fold), the potency (9.9-fold), the affinity (1.7- and 6.1-fold in competition against agonist and inverse agonist, respectively), and the efficacy (2.5-fold) of CXCL1/GROalpha [25].
• We report here that PGE2 induces expression of CXCL1 (growth-regulated oncogene alpha), a pro-angiogenic chemokine, in human CRC cells [26].

Physical interactions of CXCL1

• 125I-MGSA binding was specific and could not be displaced by unlabeled IL-8 [27].
• We show here that the CXCL1 maximal binding to CXCR2 expressed on HEK293 and CHO-K1 cells is dependent on the presence of cell surface HSPGs [22].
• Scatchard analysis of MGSA binding showed that the chemokine receptor from renal tissues had a binding affinity of 3.5 nM similar to that observed for the erythroid isoform (5-10 nM) [28].
• Receptor binding and biological studies with the alanine scan mutants of MGSA demonstrate that MGSA binds to DARC and the IL-8RB through distinct binding regions [10].

Regulatory relationships of CXCL1

• Neutrophil-activating peptide 2 and gro/melanoma growth-stimulatory activity interact with neutrophil-activating peptide 1/interleukin 8 receptors on human neutrophils [29].
• The cell surface HSPGs on cells are required for CXCL1-induced PAK1 activation [22].
• Endothelin-1 induces CXCL1 and CXCL8 secretion in human melanoma cells [30].
• We propose that the concurrence of CXCR2 on oligodendrocytes and induced CXCL1 on hypertrophic astrocytes in MS provides a novel mechanism for recruitment of oligodendrocytes to areas of damage, an essential prerequisite for lesion repair in this devastating human condition [4].
• The LMLP stimulated the early secretion of CXCL1/KC and enhanced the level of TLR2 mRNA expression in PTCs through time- and dose-dependent effect [31].

Other interactions of CXCL1

• The chemotactic response to the CXC and CC chemokines correlated with the receptor expression except that all 3 populations responded to GRO-alpha, despite their lack of CXCR2 expression [32].
• Chemokine levels in human liver homogenates: associations between GRO alpha and histopathological evidence of alcoholic hepatitis [33].
• Three of the 10 transcripts encoded CXC chemokines (CXCL1, CXCL2, and CXCL6) [34].
• ZR-75-1 responded to MIP-1beta and GRO-alpha, giving maximum migration indices of 3.7 and 5.3, respectively, and exhibited a migratory response to MIP-1alpha, IL-8 and MCP-1 although to a lower degree [35].
• Furthermore, IL-8 induced a significant increase in extracellular signal-regulated kinase 2 phosphorylation, whereas MGSA/GROalpha was much less effective [36].

Analytical, diagnostic and therapeutic context of CXCL1

• The presence of CXCL1 in the supernatants of infected cells was further demonstrated by a specific ELISA and its intracellular accumulation by flow cytometry [37].
• Quantitative real-time PCR results established expression of CXCL8, CXCL1, and HGF in all 5 cell lines tested [38].
• After intradermal injection of 200 ng/site, GCP-2 provoked a significant granulocyte infiltration, albeit to a lesser extent than did IL-8 and GRO alpha [39].
• Initial studies by cytokine protein array analysis revealed significant upregulation of neutrophil-chemoattractant keratinocyte-derived chemokine (CXCL1/KC) at nanogram range of LMLP stimulation in cultured murine proximal tubule cells (PTCs) [31].
• Reverse transcriptase polymerase chain reaction demonstrates that the class II IL-8R mRNA, which has previously been detected only in cells of hematopoietic lineage, is also expressed in non-hematopoietic cell types shown to respond to MGSA or IL-8 [40].

References