Vitamin D/VDR signaling inhibits LPS-induced IFNγ and IL-1β in Oral epithelia by regulating hypoxia-inducible factor-1α signaling pathway

Abstract

Background Oral lichen planus (OLP) is known as a chronic inflammatory disease. Our recent studies have suggested that vitamin D/vitamin D receptor (VDR) signaling exerts its protective effects on oral keratinocyte apoptosis by regulating microRNA-802 and p53-upregulated modulator of apoptosis (PUMA), but its roles in oral epithelial inflammatory responses in OLP are still unknown. Herein, we identify lipopolysaccharide (LPS) is able to enhance interferon gamma (IFNγ) and interleukin-1 beta (IL-1β) productions in human oral keratinocytes (HOKs) dependent on hypoxia-inducible factor-1α (HIF-1α). Methods HIF-1α and cytokines levels in HOKs were investigated by real-time PCR and western blotting after LPS challenge. The effects of 1,25(OH) 2 D 3 on LPS-induced HIF-1α and cytokines were tested by real-time PCR, western blotting, siRNA-interference and plasmids transfection techniques. The roles of 1,25(OH) 2 D 3 in regulating HIF-1α levels were investigated using western blotting, siRNA-interference, plasmids transfection and Chromatin Immunoprecipitation (ChIP) assays. Finally, HIF-1α, IFNγ and IL-1β expressions in oral epithelia derived from mice and individuals were measured by real-time PCR, western blotting and immunohistochemical staining. Results As a critical regulator, vitamin D suppresses LPS-induced HIF-1α to block IFNγ and IL-1β productions. Mechanistically, vitamin D inactivates nuclear factor-κB (NF-κB) pathway and up-regulates von Hippel-Lindau (VHL) levels, leading to HIF-1α reduction. Moreover, HIF-1α status of oral epithelia is elevated in VDR −/− mie as well as in VDR-deficient human biopsies, accompanied with increased IFNγ and IL-1β. Conclusion Collectively, this study uncovers an unrecognized roles of vitamin D/VDR signaling in regulating cytokines in oral keratinocytes and reveals the molecular basis of it. Electronic supplementary material The online version of this article (10.1186/s12964-019-0331-9) contains supplementary material, which is available to authorized users.

Inflammation (IL-1β) Modifies the Effect of Vitamin D and Omega-3 Long Chain Polyunsaturated Fatty Acids on Core Symptoms of Autism Spectrum Disorder—An Exploratory Pilot Study

“…Our choice of IL-1β as a marker of inflammation was based on reviews of literature reporting inflammatory markers in ASD [10,16,17], the impact of vitamin D and omega-3 LCPUFA on inflammatory markers [28,32,74], and the stability of the inflammatory markers in the blood [75]. It has been suggested that IL-1β is degraded within 2-3 years of storage.…”

Vitamin D/VDR signaling induces miR-27a/b expression in oral lichen planus

“…Herein, we focused on the mechanism of miR-27a/b reductions in OLP. www.nature.com/scientificreports www.nature.com/scientificreports/ Our recent data have indicated that vitamin D/VDR signaling plays a protective role in OLP by inhibiting cytokines secretion and apoptosis in oral keratinocytes 25,26 . In the current study, we located VDR binding sites in the promoter regions of miR-27a/b, implying vitamin D/VDR signaling possesses the potential of inducing miR-27a/b expression.…”

“…Vitamin D or VDR overexpression has been proven to perform its regulatory functions in oral epithelium of OLP by impeding nuclear factor-κB (NF-κB) pathway or by inducing von Hippel-Lindau (VHL) 25,26 . In this work, we found that either VDR plasmids transfection or vitamin D treatment attenuated LPS or activated CD4 + T cell supernatant-induced miR-27a/b decreases in OLP cell models, proposing a notion that vitamin D/VDR signaling may control miR-27a/b expression to exert its physiological actions in OLP and expand the regulatory networks of vitamin D/VDR signaling.…”

Possible role of vitamin d in pathogenesis of lichenoid dermatoses (a review of literature)

“…A recent study found that VD receptor (VDR) signaling has a protective effect on keratinocyte apoptosis in the oral cavity by regulating miRNA-802 and p53-positive apoptosis modulator (PUMA), which may be important when considering the pathogenesis of oral lichen planus (OLP) [5]. It was studied the molecular mechanisms of suppressing the expression of the in oral LP (OLP).…”

“…As a cytokine regulator, 1,25 (OH) 2D3 inhibited HIF-1α (hypoxia-induced factor-1α), which in turn blocked the production of IFNγ (interferon gamma) and IL-1β (interleukin-1 beta) in human oral keratinocytes. Given that in VDR -/ -mie, as well as in VDR-deficient human biopsies, the HIF-1α status of the oral epithelium is increased, which is accompanied by an increase in IFNγ and IL-1β, VD may play a role in the development of inflammation in OLP [5].…”