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The Endothelial Cell-Produced Antiangiogenic Cytokine Vascular Endothelial Growth Inhibitor Induces Dendritic Cell Maturation¹

University of Pittsburgh Cancer Institute and Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213

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-B, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from National Institutes of Health (CA113875 to L.-Y.L.) and the Hillman Foundation (to L.-Y.L.).

² Address correspondence and reprint requests to Dr. Lu-Yuan Li, University of Pittsburgh Cancer Institute and Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213. E-mail address: lil{at}upmc.edu

³ Abbreviations used in this paper: TNFSF, TNF superfamily; CCM, complete culture medium; DC, dendritic cell; DR3, death domain-containing receptor-3; VEGF, vascular endothelial growth factor; VEGI, vascular endothelial growth inhibitor.

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