Dehydroabietic acid reverses TNF-α-induced the activation of FOXO1 and suppression of TGF-β1/Smad signaling in human adult dermal fibroblasts

Wound healing impairment is a well-documented phenomenon in clinical and experimental diabetes, and in diabetic wound healing impaired fibroblast has been linked to increased levels of tumor necrosis factor-alpha (TNF-alpha). A number of signaling pathways including TNF-alpha/forkhead box O1 (FOXO1) and transforming growth factor-beta 1 (TGF-beta 1)/Smads in fibroblasts appear to play a cardinal role in diabetic wound healing. Dehydroabietic acid (DAA) is obtained from Commiphora oppbalsamum and inhibits the production of TNF-alpha in macrophages and adipocytes, decreases the level of TNF-alpha in obese diabetic KK-Ay mice, but its effect on diabetic wound healing is unknown. This study was to investigate the effect of DAA on TNF-alpha-stimulated human adult dermal fibroblasts. On the one hand, TNF-alpha significantly decreased the fibroblast proliferation and the expression of PCNA, Ki67 and cyclin D1, increased the fibroblast apoptosis, caspase-8/3 activity, expressions of cleaved caspase-8 and caspase-3, decreased the Bcl-2/Bax ratio and increased activation of the pro-apoptotic transcription factor FOXO1. All the above-mentioned cell responses were remarkably reversed by DAA. On the other hand, TNF-alpha also inhibited TGF-beta 1-induced the Smad3 signaling pathway what is closely related to the fibroblast migration and the differentiation of myofibroblasts. However, DAA significantly promoted the migration and increased the expression of a-smooth muscle actin and fibronectin under the stimulus of a combination of TNF-alpha and TGF-beta 1. In conclusion, DAA could reverse several cell responses stimulated by TNF-alpha, including the activation of FOXO1 and the TGF-beta 1/Smad3 signaling pathway. These results suggested that DAA could be useful in improving the diabetic wound healing.