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Daniel J. Brat, Anita C. Bellail, Erwin G. Van Meir, The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis, Neuro-Oncology, Volume 7, Issue 2, April 2005, Pages 122–133, https://doi.org/10.1215/S1152851704001061
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Abstract
Interleukin-8 (IL-8, or CXCL8), which is a chemokine with a defining CXC amino acid motif that was initially characterized for its leukocyte chemotactic activity, is now known to possess tumorigenic and proangiogenic properties as well. In human gliomas, IL-8 is expressed and secreted at high levels both in vitro and in vivo, and recent experiments suggest it is critical to glial tumor neovascularity and progression. Levels of IL-8 correlate with histologic grade in glial neoplasms, and the most malignant form, glioblastoma, shows the highest expression in pseudopalisading cells around necrosis, suggesting that hypoxia/anoxia may stimulate expression. In addition to hypoxia/anoxia stimulation, increased IL-8 in gliomas occurs in response to Fas ligation, death receptor activation, cytosolic Ca2+, TNF-α, IL-1, and other cytokines and various cellular stresses. The IL-8 promoter contains binding sites for the transcription factors NF-κB, AP-1, and C-EBP/NF-IL-6, among others. AP-1 has been shown to mediate IL-8 upregulation by anoxia in gliomas. The potential tumor suppressor ING4 was recently shown to be a critical regulator of NF-κB-mediated IL-8 transcription and subsequent angiogenesis in gliomas. The IL-8 receptors that could contribute to IL-8-mediated tumorigenic and angiogenic responses include CXCR1 and CXCR2, both of which are G-protein coupled, and the Duffy antigen receptor for cytokines, which has no defined intracellular signaling capabilities. The proangiogenic activity of IL-8 occurs predominantly following binding to CXCR2, but CXCR1 appears to contribute as well through independent, small-GTPase activity. A precise definition of the mechanisms by which IL-8 exerts its proangiogenic functions requires further study for the development of effective IL-8-targeted therapies.
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Author notes
Department of Pathology and Laboratory Medicine (D.J.B.) andLaboratory of Molecular Neuro-Oncology, Departments of Neurosurgery and Hematology/Oncology, and Winship Cancer Institute (A.C.B., E.G.V.M.), Emory University School of Medicine, Atlanta, GA 30322, USA
- angiogenesis
- cytokine
- tumor necrosis factors
- signal transduction
- interleukin-1
- hypoxia
- chemokines
- glioblastoma
- amino acid motifs
- anoxia
- binding sites
- cytosol
- tumor suppressor genes
- glioma
- guanosine triphosphate phosphohydrolases
- gtp-binding proteins
- interleukin-8
- leukocytes
- ligation
- necrosis
- neovascularization, pathologic
- transcription factor ap-1
- up-regulation (physiology)
- neoplasms
- transcription factor
- duffy antigen type
- evidence-based practice
- death domain receptors