Abstract
Psoriasis is a complex inflammatory disease characterized by hyperproliferative keratinocyte caused by active PI3K/AKT signaling. TNF-α concentrated in the psoriatic lesions stimulates AKT activation. We previously discovered that oxyresveratrol inhibited inflammation via suppressing AKT phosphorylation, therefore oxyresveratrol may possess a conserved property to block AKT activation and proliferation in keratinocyte in response to TNF-α. Our current study proved that oxyresveratrol exhibited potent anti-proliferative effects against TNF-α. These effects are explained by the findings that oxyresveratrol could potentially inhibit TNF-α-stimulated AKT and GSK3-β activation in a dose-dependent manner, and its inhibitory pattern was comparable to that of a specific PI3K inhibitor. Results from immunofluorescence supported that oxyresveratrol effectively inhibited AKT and GSK3-β activation in individual cells upon TNF-α stimulation. Furthermore, functional assay confirmed that oxyresveratrol repressed the expansion of the HaCaT colony over 3 days, and this was caused by the ability of oxyresveratrol to induce cell cycle arrest at S and G2/M phases and the reduction in the expression of a proliferative marker (Ki-67) and a survival marker (MCL-1). Given the importance of TNF-α and the PI3K/AKT pathway in the psoriatic phenotype, we anticipate that oxyresveratrol, which targets the TNF-α-stimulated PI3K/AKT pathway, would represent a promising psoriasis therapy in the near future.
Highlights
Psoriasis is well established to be an incurable chronic inflammatory dermatosis that impacts people around the globe [1,2]
Based on the results from Western blot where it showed that phosphorylation of AKT and GSK3-β (p-GSK3-β ) was peaked at 40, and 20 min after TNF-α stimulation, respectively, the harvesting time point for detecting phosphorylated AKT (pAKT) was performed at 40 min after TNF-α stimulation, whereas the time for detecting GSK3-β was at selected at 20 min post- TNF-α stimulation
TNF-α at all concentrations did not have any effect on cell cycle distribution tested by cell cycle analysis as the percentage of the cell in the G1, S, and the G2/M phase of all TNF-α-treated groups was not different (Figure 1B)
Summary
Psoriasis is well established to be an incurable chronic inflammatory dermatosis that impacts people around the globe [1,2]. TNF-α is believed to be one of the key mediators causing chronic psoriasis because it can trigger constitutive inflammatory cytokine releasing, including IL-17 and IL-23, and lead to uncontrollable cell proliferation [12]. In addition to the aspect of its inflammatory aggravation, TNF-α can stimulate the proliferation of normal healthy cells [16,17] This cytokine plays a major role in promoting the initiation and progression of cancer cells [18]. The effect of TNF-α on cell proliferation may be regulated in part through the ability of this cytokine to activate PI3K/AKT signal transduction pathway. TNF receptor activation through the NF-κB and PI3K/AKT pathways causes an increase in the production of various inflammatory cytokines and chemokines that promote cell proliferation and cell survival, leading to immune response [42,43]. We believe that oxyresveratrol is a good candidate to be developed as a promising agent targeting hyperactive PI3K/AKT pathway for the psoriasis therapy in the near future
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