Abstract
BackgroundPsoriasis is a chronic inflammatory skin disease affecting 2–3% of the population worldwide. Hyperproliferative keratinocytes were thought to be an amplifier of inflammatory response, thereby sustaining persistence of psoriasis lesions. Agents with the ability to inhibit keratinocyte proliferation or induce apoptosis are potentially useful for psoriasis treatment. 18β-Glycyrrhetinic acid (GA), an active metabolite of glycyrrhizin, exhibits diverse pharmacological activities, including anti-inflammatory, anti-bacteria and anti-proliferation. The current study aims to evaluate the effects of GA on the proliferation and apoptosis of human HaCaT keratinocytes in vitro and investigate the effects of GA on the skin lesions of imiquimod (IMQ)-induced psoriasis-like mouse model in vivo.MethodsCell viability was assayed by CCK-8. Flow cytometry was performed to measure apoptosis and reactive oxygen species (ROS), with Annexin V-FITC/PI detection kit and DCFH-DA probe respectively. Caspase 9/3 activities were measured using caspase activity assay kits. The protein levels of Akt and p-Akt were determined using Western blotting. IMQ was applied to induce psoriasis-like skin lesions in mice. The histological change in mouse skin lesions was detected using hematoxylin and eosin (H&E) staining. The severity of skin lesions was scored based on Psoriasis Area Severity Index (PASI). RT-PCR was employed to examine the relative expression of TNF-α, IL-22 and IL-17A in mouse skin lesions.ResultsGA decreased HaCaT keratinocytes viability and induced cell apoptosis in a dose-dependent manner. In the presence of GA, intracellular ROS levels were significantly elevated. NAC, a ROS inhibitor, attenuated GA-mediated HaCaT keratinocytes growth inhibition and apoptosis. In addition, GA treatment remarkably decreased p-Akt protein level, which could be restored partially when cells were co-treated with GA and NAC. LY294002 (a PI3K inhibitor) treatment significantly enhanced GA-mediated cytotoxicity. Moreover, GA ameliorated IMQ-induced psoriasis-like skin lesions in mice.ConclusionsGA inhibits proliferation and induces apoptosis in HaCaT keratinocytes through ROS-mediated inhibition of PI3K-Akt signaling pathway, and ameliorates IMQ-induced psoriasis-like skin lesions in mice.
Highlights
Psoriasis is a chronic inflammatory skin disease affecting 2–3% of the population worldwide
Glycyrrhetinic acid (GA) decreased cell viability in HaCaT keratinocytes To estimate the effect of GA on the cell viability of HaCaT keratinocytes, cells were seeded in 96-well plates and treated with the different concentrations of GA (0 for control, 10, 20, 25, 30, 35, 40, 50, 80, 100, 200 μM) for 24 h
GA induced apoptosis in HaCaT keratinocytes Flow cytometry was performed to evaluate the effect of GA on HaCaT keratinocytes apoptosis using propidium iodide (PI) and annexin V-fluorescein isothiocyanate (FITC) staining
Summary
Psoriasis is a chronic inflammatory skin disease affecting 2–3% of the population worldwide. Hyperproliferative keratinocytes were thought to be an amplifier of inflammatory response, thereby sustaining persistence of psoriasis lesions. Psoriasis is a chronic immune-mediated skin disease resulting from genetic, epigenetic and environmental factors, which is characterized by hyperproliferation and aberrant differentiation of keratinocytes, excessive infiltration of leukocytes into the dermis or epidermis. It affects 2–3% of the population worldwide [1]. Hyperproliferative keratinocytes respond to the cytokines produced by immune cells and in turn produce pro-inflammatory cytokines amplifying the local immune responses through formation of a positive feedback loop, thereby contributing to sustain persistence of psoriasis lesions [3,4,5]. Agents capable of inhibiting proliferation, inducing apoptosis of keratinocytes are potentially useful for psoriasis treatment [6,7,8,9,10]
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