Hypoxia-induced HIF-1 α accumulation is augmented in a co-culture of keloid fibroblasts and human mast cells:: Involvement of ERK1/2 and PI-3K/Akt

Keloids represent a prolonged inflammatory fibrotic state with areas that display distinctive histological features characterized by an abundant extracellular matrix stroma, a local infiltration of inflammatory cells including mast cells, and a milieu of enriched cytokines. Previous Studies front our laboratory demonstrated in intrinsic higher level of HIF-1 alpha and VEGF protein expression in keloid tissues compared with their adjacent unremarkable skins. To further investigate the mechanisms underlying the elevated expression of HIF-1 alpha and VEGF in keloids, we exposed a co-culture of keloid fibroblasts and mast cells (HMC-1) to hypoxic conditions and studied the expression of HIF-1 alpha and its target gene, VEGF. Our results showed that hypoxia-dependent HIF-1 alpha protein accumulation and VEGF expression is augmented in keloid fibroblasts when co-cultured with HMC-1 Cells under file condition where direct cell-cell contact is allowed. But such augmentation is not observed in the transwell co-culture system Whereas fibroblasts and HMC-1 cells were separated by a porous Membrane. Our results also indicated that the enhancement of hypoxia-mediated activation of ERK1/2 and Akt requires direct cell-cell interaction between mast cells and keloid fibroblasts, and activation of both ERK1/2 and Akt is involved in the hypoxia-dependent HIF-1 alpha protein accumulation and VEGF expression in the co-culture system. These Findings Suggest that under hypoxic conditions mast cells may contribute, at least in part, to an elevated expression of HIF-1 alpha and VEGF protein in keloids via direct cell-cell interaction with fibroblasts. (c) 2005 Elsevier Inc. All rights reserved.