IL-8 Directly Enhanced Endothelial Cell Survival, Proliferation, and Matrix Metalloproteinases Production and Regulated Angiogenesis

Abstract

IL-8, a member of the chemokine family, has been shown to play an important role in tumor growth, angiogenesis, and metastasis. The objective of this study was to determine the mechanism of IL-8-mediated angiogenesis. We examined the direct role of IL-8 in angiogenesis by examining IL-8 receptor expression on endothelial cells and their proliferation, survival, and matrix metalloproteinases (MMPs) production. We demonstrate that HUVEC and human dermal microvascular endothelial cells constitutively express CXCR1 and CXCR2 mRNA and protein. Recombinant human IL-8 induced endothelial cell proliferation and capillary tube organization while neutralization of IL-8 by anti-IL-8 Ab blocks IL-8-mediated capillary tube organization. Incubation of endothelial cells with IL-8 inhibited endothelial cell apoptosis and enhanced antiapoptotic gene expression. Endothelial cells incubated with IL-8 had higher levels of Bcl-xL:Bcl-xS and Bcl-2:Bax ratios. Furthermore, incubation of endothelial cells with IL-8 up-regulated MMP-2 and MMP-9 production and mRNA expression. Our data suggest that IL-8 directly enhanced endothelial cell proliferation, survival, and MMP expression in CXCR1- and CXCR2-expressing endothelial cells and regulated angiogenesis.

Chemokines in tumor angiogenesis and metastasis

“…Furthermore, it was shown that CXCL8 can act directly on vascular endothelial cells by promoting their survival [78]. Studies from our lab and other groups suggest that CXCL8 stimulates both endothelial proliferation and capillary tube formation in vitro in a dose dependent manner, and both of these effects can be blocked by monoclonal antibodies to CXCL8 [79,80]. In addition, CXCL8 was shown to inhibit apoptosis of endothelial cells [81].…”

Activation of the Nrf2/antioxidant response pathway increases IL-8 expression

“…These showed that IL-8 suppresses neutrophil adhesion to activated endothelium [27,28], and that elevated intravascular levels of IL-8 block neutrophil emigration to sites of inflammation [28][29][30]. Additionally, the endothelial isoform of IL-8 appears to have a variety of tissue-protective effects, such as mediating normal wound healing, decreasing scar formation, tissue remodeling through endothelial proliferation, myocardial protection during ischemiareperfusion injury, and maintenance of normal glomerular architecture [31][32][33][34]. Finally, neutrophils from patients with active SLE demonstrate a defect in IL-8 production that resolves with successful therapy [35].…”

Biology of Cerebral Arteriovenous Malformations with a Focus on Inflammation

“…MIF, Caspase-3, MMP-9, IL-6, TNF-α, and VEGF 23,39,40,64 Decreased TIMP level 30 Macrophage recruitment 39 ECM degradation 40 Increased EC growth 43 Vascular permeability VEGF 68 EC fenestrations ECM degradation [65][66][67]77 Sprouting angiogenesis 69 HCSMC proliferation IL-6 23 Upregulation of VEGF and MMP-9 23 CAM, cell adhesion molecule; EC, endothelial cell; 90 ECM, extracellular matrix; HCSMC, human cerebral smooth muscle cell; HIF-1, hypoxia-inducible factor-1; ICAM-1, intercellular cell adhesion molecule-1; IL-6, interleukin-6; IL-1, interleukin-1; IL-8, interleukin-8; IL-1β, interleukin-1-beta; MIF, macrophage migration inhibitory factor; MMP, matrix metalloproteinase; NF-κB, nuclear factor-kappa B; TIMP, tissue inhibitor of metalloproteinase; TNF-α, tumor necrosis factor-alpha; VCAM-1, vascular cell adhesion molecule-1; VEGF, vascular endothelial growth factor.…”