Angiogenic Effects of Interleukin 8 (CXCL8) in Human Intestinal Microvascular Endothelial Cells Are Mediated by CXCR2

Heidemann, Jan; Ogawa, Hitoshi; Dwinell, Michael B.; Rafiee, Parvaneh; Maaser, Christian; Gockel, Henning R.; Otterson, Mary F.; Ota, David M.; Lügering, Norbert; Domschke, Wolfram; Binion, David G.

doi:10.1074/jbc.m208231200

Cited by 425 publications

(342 citation statements)

References 70 publications

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“…The role of each of these receptors in IL-8-mediated activity remains controversial. Previous studies have shown that the angiogenic effects of IL-8 in human microvascular endothelial cells and NSCLC were mediated by CXCR2 (Addison et al, 2000;Salcedo et al, 2000;Heidemann et al, 2003). The chemotactic response of melanoma cells to IL-8 was mediated by CXCR1 (Ramjeesingh et al, 2003), and the mitogenic activity of IL-8 was mediated by both CXCR1 and CXCR2 in colon cancer (Li et al, 2001), but only by CXCR1 in monocytes (Browning et al, 2000).…”

Section: Discussionmentioning

confidence: 95%

Interleukin-8/CXCL8 is a growth factor for human lung cancer cells

et al. 2004

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Interleukin-8/CXCL8 (IL-8) is a chemokine and angiogenic factor. Recently, IL-8 was identified as an autocrine growth factor in several human cancers. Here, we investigated the expression and function of IL-8 in lung cancer cells. The expressions of IL-8 and its receptors, CXCR1 and CXCR2, were examined in a panel of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines. Using reverse transcription -polymerase chain reaction (RT -PCR) and enzyme-linked immunosorbent assay, we found that all NSCLC cell lines tested produced modest or high levels of IL-8 (up to 51 ng ml À1 10 6 cells À1 ). Expression of CXCR1 and CXCR2 was found by RT -PCR and flow cytometry in two out of three cell lines. In contrast, SCLC cell lines produced very low or undetectable levels of IL-8, but expressed CXCR1 and CXCR2. We next investigated whether IL-8 could act as an autocrine growth factor in two NSCLC cell lines (H460 and MOR/P) expressing both IL-8 and its receptors. We found that cell proliferation was attenuated by anti-IL-8 neutralising antibody to 71 and 76% in H460 and MOR/P, respectively (Po0.05). Exogenous IL-8 significantly stimulated cell proliferation in four SCLC cell lines tested in a dose-dependent fashion. Cell proliferation was increased by between 18% (Po0.05) and 37% (Po0.05). Stimulation of cell proliferation by IL-8 was also demonstrated by analysis of proliferating cell nuclear antigen expression and cell cycle in H69 cells. Furthermore, we investigated which receptor(s) mediated the mitogenic function of IL-8 in lung cancer cells. We found that cell proliferation was significantly reduced by anti-CXCR1 antibody but not by anti-CXCR2 antibody. In conclusion, IL-8 can act as an autocrine and/or paracrine growth factor for lung cancer cells, and the mitogenic function of IL-8 in lung cancer is mediated mainly by CXCR1 receptor.

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Section: Discussionmentioning

confidence: 95%

Interleukin-8/CXCL8 is a growth factor for human lung cancer cells

et al. 2004

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“…Gemcitabine induced a robust production of CXCL8 in Miapaca-2 and Panc-1 cells. This chemokine can promote the migration and proliferation of endothelial cells, after binding mainly CXCR2 expressed by endothelial cells [27,28]. Moreover, accumulating evidence indicates the crucial roles of CXCL8 in tumor neovascularization in several animal tumor models, as evidenced by reduced tumor angiogenesis by CXCL8 blockade [29,30].…”

Section: Discussionmentioning

confidence: 99%

Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization

Song

Baba

et al. 2015

Biochemical and Biophysical Research Communications

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a b s t r a c tPatients with pancreatic ductal adenocarcinoma (PDAC) are frequently complicated with metastatic disease or locally advanced tumors, and consequently need chemotherapy. Gemcitabine is commonly used for PDAC treatment, but with limited efficacy. The capacity of gemcitabine to generate reactive oxygen species (ROS) in human pancreatic cancer cells, prompted us to examine its effects on the expression of pro-inflammatory cytokines and chemokines. We observed that gemcitabine enhanced selectively the expression of CXCL8 in human pancreatic cancer cells through ROS generation and NF-kB activation. In vitro blocking of CXCL8 failed to modulate gemcitabine-mediated inhibition of cell proliferation in human pancreatic cancer cells. Gemcitabine also enhanced CXCL8 expression in pancreatic cancer cells in xenografted tumor tissues. Moreover, anti-CXCL8 antibody treatment in vivo attenuated tumor formation as well as intra-tumoral vascularity in nude mice, which were transplanted with Miapaca-2 cells and treated with gemcitabine. Thus, gemcitabine-induced CXCL8 may counteract the drug through inducing neovascularization.

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“…The constitutive chemokine ligand CXCL12 and its cognate receptor CXCR4 are evolutionarily conserved and essential for life in mice (Nagasawa et al, 1996a, b). Homeostatic roles for CXCL12 signaling through CXCR4 in various physiological compartments have been described, including B-cell development, gastrointestinal vascularization, heart and cerebral development, as well as mucosal epithelial wound healing (Nagasawa et al, 1996a;Tachibana et al, 1998;Zou et al, 1998;Heidemann et al, 2003;Smith et al, 2005;Moyer et al, 2007). Thus, CXCL12 and CXCR4 are widely expressed throughout the body and serve diverse physiological roles depending on the tissue or cell type.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells

2007

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Expression of the chemokine receptor CXCR4 has been linked with increased metastasis and decreased clinical prognosis in breast cancer. The current paradigm dictates that CXCR4 fosters carcinoma cell metastasis along a chemotactic gradient to organs expressing the ligand CXCL12. The present study asked if alterations in autocrine CXCR4 signaling via dysregulation of CXCL12 in mammary carcinoma cells modulated their metastatic potential. While CXCR4 was consistently detected, expression of CXCL12 characteristic of human mammary epithelium was silenced by promoter hypermethylation in breast cancer cell lines and primary mammary tumors. Stable re-expression of functional CXCL12 in ligand null cells increased orthotopic primary tumor growth in the mammary fat-pad model of tumorigenesis. Those data parallel increased carcinoma cell proliferation measured in vitro with little-to-no-impact on apoptosis. Moreover, re-expression of autocrine CXCL12 markedly reduced metastatic lung invasion assessed using in vivo bioluminescence imaging following tail vein injection. Consistent with those data, decreased metastasis reflected diminished intracellular calcium signaling and chemotactic migration in response to exogenous CXCL12 independent of changes in CXCR4 expression. Together these data suggest that an elevated migratory signaling response to ectopic CXCL12 contributes to the metastatic potential of CXCR4-expressing mammary carcinoma cells, subsequent to epigenetic silencing of autocrine CXCL12.

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Angiogenic Effects of Interleukin 8 (CXCL8) in Human Intestinal Microvascular Endothelial Cells Are Mediated by CXCR2

Cited by 425 publications

References 70 publications

Interleukin-8/CXCL8 is a growth factor for human lung cancer cells

Interleukin-8/CXCL8 is a growth factor for human lung cancer cells

Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization

Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells

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