Abstract
The suppressive function of vitamin D on oral lichen planus (OLP) have been documented previously. Vitamin D receptor (VDR) expression is down-regulated in OLP, but the molecular mechanism of its decrease and the related anti-inflammatory contributor of epithelial VDR signaling is unclear. Herein, we demonstrated that lipopolysaccharide (LPS) remarkedly down-regulated VDR expression of keratinocytes, and the reduced regulation was dependent on tumor necrosis factor alpha (TNFα)-miR-346 pathway. In human specimen studies, VDR levels of oral mucosal epithelia from OLP patients decreased substantially accompanied with robust TNFα and miR-346 induction, compared to the normal tissues. In addition, vitamin D/VDR signaling inhibited LPS-induced p53-upregulated modulator of apoptosis (PUMA) induction in keratinocytes via impeding nuclear factor-κB (NF-κB) activation, resulting in keratinocytes apoptosis reduction. Importantly, PUMA activity was up-regulated strongly in diseased epithelium, reversely correlated with VDR expression. Totally, our data indicate that LPS is responsible for VDR downregulation in oral keratinocytes, which is associated with OLP development.
Highlights
Previous studies have provided compelling evidence that CD4+ and CD8+ T cells, trigged by multiple intrinsic or extrinsic etiological factors, are the major mediators in the inflammatory response of OLP8–10
Since intestinal epithelial vitamin D receptor (VDR) signaling maintains the integrity of gut mucosal barrier dependent on inhibiting cell apoptosis and regulating tight junction of epithelium[19,21], we propose that VDR located in oral epithelium might preserve mucosal homeostasis as well
We demonstrate that LPS-induced VDR down-regulation enhances p53-upregulated modulator of apoptosis (PUMA) levels (Fig. 6), promoting epithelial cells apoptosis and impairing mucosal barrier
Summary
Previous studies have provided compelling evidence that CD4+ and CD8+ T cells, trigged by multiple intrinsic or extrinsic etiological factors, are the major mediators in the inflammatory response of OLP8–10. The histological characteristics of disrupted epithelium of OLP caused by bacteria or inflammatory reaction, such as apoptosis, atropy and liquefaction, indicate mucosal epithelial barrier impairment[13]. Inflammatory reaction causes apoptosis of epithelia[16], in turn, excessive loss of these cells accelerates invasion of oral bacteria and antigen. This vicious circle leads to the clinical manifestations of OLP . Despite we confirmed that vitamin D plays its protective role in OLP through mediating nuclear factor-κB (NF-κB) signaling pathway, the function of epithelial VDR of oral mucosa remains elusive, requiring more investigations. Local VDR reduction in epithelium, due to inflammation-induced chemokines or lipopolysaccharide (LPS)-induced cytokines partially, might compromise epithelial protective function and accelerate the onset of OLP
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