Abstract
New therapeutic strategies and the development of treatments against inflammatory bowel disease (IBD) require the initiation of immune tolerance and inhibition of excessive inflammation. Resveratrol, a polyphenolic compound, is a powerful immunosuppressor, but it can lead to apoptotic death of normal cells at high concentrations. When we induced a structural modification of resveratrol by gamma irradiation, we were able to investigate the potential tolerogenic and anti-inflammatory effect of a new radiolysis product (named γ-Res) during dendritic cell (DC) activation/differentiation. The potential tolerogenic and anti-inflammatory effect of γ-Res were investigated by cytokine secretion, surface molecule expression, antigen uptake ability, antigen presenting ability, signaling pathway, and mixed lymphocyte reaction (MLR) assay using enzyme-linked immunosorbent assay (ELISA), western blot and flow cytometry. LPS-activated DCs treated with γ-Res exhibited alterations in their mature and functional statuses including a strongly inhibited cytokine production, surface molecule expression, antigen-presenting ability, and activated DC-induced T cell proliferation/activation. In addition, the DCs generated by the γ-Res treatment during DC differentiation induced a decreased surface molecule expression and increased IL-10 production without altering the levels of TNF-α and IL-12p70, thereby promoting the inhibition of T cell proliferation/activation and the induction of regulatory T cells via interaction with DCs in vitro. Furthermore, in the in vivo DSS-induced colitis model, γ-Res treatment conferred protective immunity with a decrease in IFN-γ+CD4+ and IL-17A+CD4+ T cells and imparted protection by reducing the disease activity and histological disease score and increasing the survival rate in dextran sulfate sodium (DSS)-induced colitis in mice. Thus, our results suggest that γ-Res may be an excellent candidate for use in IBD treatment.
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