Vascular endothelial growth factor induces protein kinase D-dependent production of proinflammatory cytokines in endothelial cells

Abstract

Emerging evidence indicates that vascular endothelial growth factor (VEGF) plays a critical role in host inflammatory responses in several disease states, including atherosclerosis, sepsis, and rheumatoid arthritis. In this study, we determined the effect of VEGF on endothelial induction of proinflammatory cytokines and investigated the responsible signal pathways. By using a cytokine antibody array that detects the end point protein products released from endothelial cells (ECs), we found that VEGF, via VEGF receptor 2 (VEGFR2), predominantly induced the production of proinflammatory cytokine interleukin (IL)-6 and CXC chemokines IL-8 and growth-related oncogene-α (GRO-α) in ECs but not in leukocytes among 36 cytokines in the array. The production of these inflammatory cytokines by VEGF was much stronger than the induction of cell adhesion molecule in ECs. We further found that the cytokine production by VEGF was essentially mediated by the Gö-6976-sensitive protein kinase D (PKD) family kinases. Importantly, the VEGF-induced production of IL-6, IL-8, and GRO-α was inhibited ∼70%, 40%, or 37% by PKD1 silencing (more than 90% knockdown) with three small interference RNAs that target different PKD1 regions. Moreover, silencing PKD2 downregulated VEGFR2 and markedly inhibited the cytokine production by VEGF in ECs. Our results indicate that VEGF, via VEGFR2-PKD1 axis, induces the production of proinflammatory cytokine IL-6, IL-8, and GRO-α in ECs but not in leukocytes, which may offer new insights into the mechanism of the proinflammatory activity of VEGF.

Cytokines and their Role in Health and Disease: A Brief Overview

“…VEGF via VEGF receptor2 predominantly induces the production of pro-inflammatory cytokines IL-6, IL-8 and growth related oncogene-alpha in endothelial cells. So, this explains a new insight into the mechanism of the proinflammatory activity of VEGF in host inflammatory responses in several disease states [26].…”

“…VEGF via VEGF receptor2 predominantly induces the production of pro-inflammatory cytokines IL-6, IL-8 and growth related oncogene-alpha in endothelial cells. So, this explains a new insight into the mechanism of the proinflammatory activity of VEGF in host inflammatory responses in several disease states [26].Arsenicosis is a multisystem disorder that has been linked to hyperkeratosis and skin cancer. Cutaneous toxicity is a related effect of various cytokines like IL-8, TGF-β, TNF-α and GM-CSF.…”

Protein Kinase D Promotes Airway Epithelial Barrier Dysfunction and Permeability through Down-regulation of Claudin-1

“…1D). Gö6976 is an inhibitor of PKD and classical PKC isoforms and has been widely used as a PKD inhibitor for intact cell studies (29,44,45). These findings indicate that inhibition of PKD activity increases TEER of 16HBE14oϪ cell monolayers and suggest that PKD may be a negative regulator of epithelial barrier integrity.…”

“…These findings suggest a functional differentia among PKD isoforms. We have reported that PKD1 regulates the production of proinflammatory cytokines by vascular endothelial growth factor (VEGF) in endothelial cells (29) and that PKD2 is pivotal for angiogenesis (30). We also found that both PKD2 and PKD3 were novel growth regulators in triple-negative breast cancer cells (31).…”

Vitreous levels of interleukine-8 and monocyte chemoattractant protein-1 in macular oedema with branch retinal vein occlusion

“…30 We believe that thrombosis may be the stimulating agent for the increased levels of both chemokines. Moreover, previous reports have shown that retinal ischaemia stimulates IL-8 and MCP-1 production, and both chemokines are involved in retinal neovascularization.…”