Abstract
Rottlerin is a natural polyphenolic compound that was initially indicated as a PKCδ inhibitor. However, it was recently revealed that it may target a number of molecules and have biological effects on various cell types and is considered as a possible agent for tumor and cell proliferative diseases. Psoriasis is a chronic inflammatory cutaneous disorder with undefined etiology and is characterized by abnormal cellular proliferation, angiogenesis, and inflammation. Therefore, this paper investigates the regulatory effects of rottlerin on normal human epidermal keratinocytes (NHEKs) and imiquimod (IMQ)-induced psoriasiform (IPI) lesions. In vitro results showed that rottlerin inhibited cell proliferation in NHEKs through growth arrest and NFκB inhibition. It may also induce apoptosis in an autophagy-dependent pathway. We found that rottlerin inhibited human microvascular endothelial cells tube formation on matrigel. Rottlerin also decreased the cell senescence of keratinocytes and intracellular ROS generation, which indicated its antioxidant effect. We also showed that rottlerin affects the expression of keratinocyte proliferation biomarkers. In 12-O-tetradecanoylphorbol13-acetate (TPA)–induced keratinocytes, rottlerin significantly inhibited the expression of the induced pro-inflammatory cytokines in keratinocytes. An animal experiment provided the corresponding evidence based on this evidence in vitro, by using IPI model, we found that rottlerin could relieve the psoriasiform of BALB/c mice by inhibiting keratinocyte proliferation, inflammatory cell infiltration, and vascular proliferation. In conclusion, our results suggest that rottlerin may prove useful in the development of therapeutic agents against psoriasis. However, the deep mechanism still requires further study.
Highlights
Psoriasis is considered as a common inflammatory diseases of the skin that is largely driven by Th17 T-cells[1]
We further investigated the ultra-structural alterations of normal human epidermal keratinocytes (NHEKs) treated with rottlerin using Transmission electron microscopy (TEM)
Since cell senescence is considered associated with intracellular reactive oxygen species (ROS) generation, the present study further examined whether rottlerin could inhibit ROS generation in NHEKs
Summary
Psoriasis is considered as a common inflammatory diseases of the skin that is largely driven by Th17 T-cells[1]. It is characterized with hyper-proliferation and abnormal differentiation of epidermal keratinocytes, increased vascularization of the skin and inflammatory cell infiltration[2, 3]. Rottlerin in psoriasis production of several inflammatory mediators from immune cells such as TNF-α, IL-6, IL-17, IL-22 and IL-23 are confirmed to play a key role in psoriasis[1, 2, 4, 5]. Involucrin and loricrin are both proteins play key role in formation of the skin barrier and terminal differentiation of epidermis[8]. The expression of loricrin was found to be decreased in lesional and non-lesional skin of psoriasis in comparison with normal skin[11]
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