© 2005 by the Society forNeuro-Oncology
The role of interleukin-8 and its receptors in gliomagenesis and tumoralangiogenesis
Department of Pathology and Laboratory Medicine(D.J.B.) and Laboratory of Molecular Neuro-Oncology,Departments of Neurosurgery and Hematology/Oncology, and Winship CancerInstitute (A.C.B., E.G.V.M.), Emory University School of Medicine, Atlanta, GA30322, USA
2 Send correspondence to Erwin G. Van Meir, Laboratory of MolecularNeuro-Oncology, Winship Cancer Institute, Emory University School of Medicine,1365-C Clifton Road NE, Room C-5078, Atlanta, GA 30322, USA(evanmei{at}emory.edu).
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Abstract |
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Interleukin-8 (IL-8, or CXCL8), which is a chemokine with a defining CXCamino acid motif that was initially characterized for its leukocytechemotactic activity, is now known to possess tumorigenic and proangiogenicproperties as well. In human gliomas, IL-8 is expressed and secreted at highlevels both in vitro and in vivo, and recent experiments suggest it iscritical to glial tumor neovascularity and progression. Levels of IL-8correlate with histologic grade in glial neoplasms, and the most malignantform, glioblastoma, shows the highest expression in pseudopalisading cellsaround necrosis, suggesting that hypoxia/anoxia may stimulate expression. Inaddition to hypoxia/anoxia stimulation, increased IL-8 in gliomas occurs inresponse to Fas ligation, death receptor activation, cytosolicCa2+, TNF-
, IL-1, and other cytokines and various cellularstresses. The IL-8 promoter contains binding sites for the transcriptionfactors NF-
B, AP-1, and C-EBP/NF-IL-6, among others. AP-1 has beenshown to mediate IL-8 upregulation by anoxia in gliomas. The potential tumorsuppressor ING4 was recently shown to be a critical regulator ofNF-B-mediated IL-8 transcription and subsequent angiogenesis ingliomas. The IL-8 receptors that could contribute to IL-8-mediated tumorigenicand angiogenic responses include CXCR1 and CXCR2, both of which are G-proteincoupled, and the Duffy antigen receptor for cytokines, which has no definedintracellular signaling capabilities. The proangiogenic activity of IL-8occurs predominantly following binding to CXCR2, but CXCR1 appears tocontribute as well through independent, small-GTPase activity. A precisedefinition of the mechanisms by which IL-8 exerts its proangiogenic functionsrequires further study for the development of effective IL-8-targetedtherapies.
Received November 16, 2004; Accepted January 10, 2005
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