VEGF Induces IL-23 Expression in Keratinocytes through p38 Signaling

Abstract

Background: Psoriasis is a chronic inflammatory skin disorder which is associated with increased cutaneous vascular endothelial growth factor (VEGF) expression. Several studies demonstrate that VEGF plays an important role in psoriasis pathogenesis by linking angiogenesis and inflammation. We aimed to study the molecular functions of VEGF in psoriasis and dissect a link between VEGF and pro-inflammatory cytokine expression in human keratinocytes. Methods: VEGF expression was evaluated in sections from lesional psoriatic skin by immunohistochemistry. Cultured keratinocytes were transfected with a VEGF expression plasmid and changes in pro-inflammatory cytokine expression were investigated by qPCR, ELISA and dot-blot. Protein phosphorylation profiles in lysates from cells overexpressing VEGF were analysed to identify the underlying signaling pathways. Specific inhibitors or siRNA knockdown were used in confirmatory experiments. Results: In lesional psoriatic skin, VEGF and the pro-inflammatory cytokine IL-23 are both strongly expressed by epidermal keratinocytes. VEGF over-expression in cultured keratinocytes resulted in increased IL-23 and IL-6 mRNA transcript abundance and protein expression. At the same time VEGF over-expression strongly increased phosphorylation of p38 MAPK, CREB and HSp27. Inhibition of p38 MAPK by SB203580 blocked VEGF induced IL-23 expression while siRNA mediated knockdown of CREB or HSp27 showed no effect. Conclusions: VEGF up-regulates pro-inflammatory IL-23 and IL-6 secretion through p38 MAPK in epidermal keratinocytes in psoriasis. Targeting VEGF and/or p38 MAPK could lead to novel anti-inflammatory treatments for this chronic skin disease.