Identification of 14-dehydroergosterol as a novel anti-inflammatory compound inducing tolerogenic dendritic cells

Abstract

Tolerogenic dendritic cells (DCs) have the ability to induce regulatory T cells and play an important role in preventing chronic inflammatory and autoimmune diseases. We have identified a novel compound, 14-dehydroergosterol, from Koji, a Japanese traditional food material fermented with fungi. 14-dehydroergosterol is an ergosterol analogue with a conjugated double bond, but the activity of 14-dehydroergosterol is much higher than that of ergosterol. 14-dehydroergosterol induces the conversion of murine bone marrow (BM)-derived DCs and differentiated DCs into tolerogenic DCs, in which the production of IL-12 is suppressed and that of IL-10 is increased. In a co-culture experiment, DCs treated with 14-dehydroergosterol induced the conversion of naïve CD4-positive T cells into regulatory T cells. In a murine model of multiple sclerosis, experimental autoimmune encephalopathy, 14-dehydroergosterol suppressed the clinical score and inflammatory responses of myeloid DCs and T cells to myelin oligodendrocyte glycoprotein. 14-dehydroergosterol-treated human DCs induced from PBMCs also showed a tolerogenic phenotype. This is the first report to identify a novel compound, 14-dehydroergosterol, that induces DCs to convert to a tolerogenic type. 14-dehydroergosterol is contained in various fermented foods based on Koji, so 14-dehydroergosterol might be a helpful aid to prevent chronic inflammatory and autoimmune diseases.

Improvement of skin conditions by ingestion of <em>Aspergillus kawachii </em>(Koji) extract containing 14-dehydroergosterol in a randomized, double-blind, controlled trial

“…The cultivated fungus body of Aspergillus kawachii was first extracted with 59% ethanol; then, rapeseed oil was added, and the oil fraction was collected as Koji extract. The concentration of 14-DHE in the Koji extract was determined by high-performance liquid chromatography (Shimadzu, Kyoto, Japan) using a C30-UG-5 column (Develosil, 10 mm × 250 mm; Nomura Chemical Co. Ltd., Aichi, Japan) with an acetonitrile–isopropanol (99:1) gradient as described by Ano et al 21 The nutritional content of this sample was: energy, 1.8 kcal; lipids, 0.2 g; and carbohydrate, protein, alcohol, moisture, and ash, 0 g per capsule.…”

“…In a previous study, injection of 14-DHE in mice significantly improved the clinical score and inflammatory response in a model of multiple sclerosis (experimental autoimmune encephalopathy). 20 , 21 Additionally, 14-DHE suppressed the inflammatory phenotype in dendritic cells derived from human peripheral blood mononuclear cells in response to lipopolysaccharide and interferon-γ stimulation. 21 Furthermore, 14-DHE has been shown in vitro to protect keratinocytes against UVA radiation.…”

“…20 , 21 Additionally, 14-DHE suppressed the inflammatory phenotype in dendritic cells derived from human peripheral blood mononuclear cells in response to lipopolysaccharide and interferon-γ stimulation. 21 Furthermore, 14-DHE has been shown in vitro to protect keratinocytes against UVA radiation. 23 …”

“… 19 Recently, we identified 14-dehydroergosterol (14-DHE, C 28 H 42 O) from Aspergillus awamori as a novel anti-inflammatory agent that induces regulatory T cells. 20 , 21 14-DHE was initially isolated as by-product in cultures of Aspergillus niger ; 22 however, no biological activity was reported. In a previous study, injection of 14-DHE in mice significantly improved the clinical score and inflammatory response in a model of multiple sclerosis (experimental autoimmune encephalopathy).…”

Medical Application of Substances Derived from Non-Pathogenic Fungi Aspergillus oryzae and A. luchuensis-Containing Koji

“…It was found that Aspergillus luchuensis mut. kawachii produces 14-dehydroergosterol ( Figure 11 ) as an anti-inflammatory substance that induces tolerogenic dendritic cells [ 82 ]. Moreover, koji extract containing 14-dehydroergosterol produced by Aspergillus luchuensis mut.…”