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.
Highlights
Dendritic cells (DCs) comprise a heterogeneous population of professional antigen-presenting cells that potently stimulate innate primary immune responses and possess the ability to regulate both innate and adaptive immunity[1,2,3,4]
As a result of searching for materials inducing tolerogenic dendritic cells (DCs), the whole extract from wheat bran fermented with Aspergillus awamori was found to lead to reduced IL-12p40 production (Fig. 1A) and increased IL-10 production (Fig. 1B) in response to LPS stimulation in bone marrow (BM)-derived myeloid DCs (mDCs)
To identify the compound responsible for these changes, the extract from wheat bran fermented with Aspergillus awamori was fractionated by HPLC, and the fraction displaying the strongest suppression of the production of IL-12p40 and the expression of I-A/I-E, CD86 and CD80 was re-fractionated
Summary
Dendritic cells (DCs) comprise a heterogeneous population of professional antigen-presenting cells that potently stimulate innate primary immune responses and possess the ability to regulate both innate and adaptive immunity[1,2,3,4]. Other than retinoic acids[20,21], few compounds that induce Tregs, especially compounds derived from food components that are easy to consume in daily life, have been reported. Owing to their potential health benefits, Japanese food products are receiving increasing attention worldwide; the health-promoting mechanisms and responsible ingredients in Japanese traditional foods have not been sufficiently elucidated. We evaluated the ability of various food materials to induce the conversion of bone marrow (BM)-derived cells into tolerogenic DCs, thereby identifying the Japanese traditional food material Koji, which comprises a cereal crop such as rice, wheat, and soy that has been fermented with fungi. We have investigated the properties of 14-DHE from Koji and elucidated its functional ability in the prevention of autoimmune and chronic inflammatory disease
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