The Endothelial Cell-Produced Antiangiogenic Cytokine Vascular Endothelial Growth Inhibitor Induces Dendritic Cell Maturation

Abstract

Angiogenesis is an essential component of chronic inflammation that is linked to carcinogenesis. In this study, we report that human vascular endothelial growth inhibitor (VEGI, TNF superfamily 15), an endothelial cell-produced antiangiogenic cytokine, induces mouse dendritic cell (DC) maturation, a critical event in inflammation-initiated immunity. VEGI-stimulated bone marrow-derived immature DCs display early activation of maturation signaling molecules NF-κB, STAT3, p38, and JNK, and cytoskeleton reorganization and dendrite formation. The activation signals are partially inhibited by using a neutralizing Ab against death domain-containing receptor-3 (DR3) or a truncated form of DR3 consisting of the extracellular domain, indicating an involvement of DR3 in the transmission of VEGI activity. A VEGI isoform, TL1A, does not induce similar activities under otherwise identical experimental conditions. Additionally, the cells reveal significantly enhanced expression of mature DC-specific marker CD83, secondary lymphoid tissue-directing chemokine receptor CCR7, the MHC class-II protein (MHC-II), and costimulatory molecules CD40, CD80, and CD86. Functionally, the cells exhibit decreased Ag endocytosis, increased cell surface distribution of MHC-II, and increased secretion of IL-12 and TNF. Moreover, VEGI-stimulated DCs are able to facilitate the differentiation of CD4+ naive T cells in cocultures. These findings suggest that the anticancer activity of VEGI arises from coupling the inhibition of endothelial cell growth with the promotion of the adaptive immune mechanisms through the stimulation of DC maturation.

Vascular endothelial growth inhibitor in human cancer (Review)

“…However, no significant correlations were observed between VEGI expression and tumour grade, TNM classification, or nodal involvement (9). It is plausible that the pro-apoptotic effect of soluble VEGI in endothelial cells is critical for its anti-tumour activity (10,(19)(20)(21)(22)28,32,33). However, it is unclear whether other mechanisms, such as activation of tumourspecific or non-specific B or T lymphocytes or induction of cytokines (18), also operate in the soluble VEGI-mediated tumour suppression.…”

“…However, these functions are inhibited in the presence of a decoy receptor (DcR3, also known as TR6, or TNFRSF21), which competes for the binding of VEGI 251 (20,24,34). Upon binding to DR3, VEGI 251 directly stimulates DC maturation, which is an essential component of host immunity against cancer development (33). Collectively, it suggests that VEGI 251 plays a central role in the interaction between the endothelium and the immune system to modulate angiogenesis and inflammation toward the suppression of tumour development and progression.…”

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

“…STAT3 was shown to be activated by EPO-R signaling (Richmond et al, 2005), yet via a distinct mechanism from STAT5 (Kirito et al, 2002). While STAT3 activation is not crucial for EPO-R activity (Menon et al, 2006), and its role in erythropoiesis is still not clear, it plays a prominent role in development and maturation 19 of DCs (Laouar et al, 2003;Tian et al, 2007). In that respect, STAT5 signaling is associated with inhibition of DC development (Esashi et al, 2008).…”

VEGI-armed oncolytic adenovirus inhibits tumor neovascularization and directly induces mitochondria-mediated cancer cell apoptosis

“…The anticancer activity of VEGI has been mostly ascribed to its ability to inhibit neovascularization by inducing apoptosis in proliferating endothelial cells [10,23], and to activate T cells, natural killer cells and dendritic cells [13,24]. These activities rely on an autocrine mechanism for the largely endothelial cell-produced cytokines to act on endothelial cells themselves, and a paracrine mechanism to act on the immune cells.…”

“…Reduced VEGI expression is reported to be associated with poor prognosis in breast cancer patients [11]. Other npg activities of VEGI also have been reported, including the stimulation of T-cell activation [12] and dendritic cell maturation [13]. Moreover, TNFSF15 single nucleotide polymorphisms are suggested to contribute to the susceptibility of inflammatory bowel disease [14,15].…”