Administration of Interleukin-35-Conditioned Autologous Tolerogenic Dendritic Cells Prolong Allograft Survival After Heart Transplantation

• Main Authors: Xianglan Liu, Yong Sun, Yang Zheng, Maomao Zhang, Xiangyuan Jin, Kai Kang, Yongshun Wang, Shuang Li, Hanlu Zhang, Qi Zhao, Shengnan Zhang, Jian Wu, Bo Yu
• Format: Article
• Language: English
• Published: Cell Physiol Biochem Press GmbH & Co KG 2018-09-01
• Series: Cellular Physiology and Biochemistry
• Subjects: Interleukin-35; Dendritic cells; Regulatory T cells; Let-7i; Transplant immunity
• Online Access: https://www.karger.com/Article/FullText/493298
• ISSN: 1015-8987; 1421-9778

Background/Aims: IL-35, a powerful suppressor of inflammation and autoimmunity, is primarily secreted by regulatory T cells (Tregs) and can, in turn, promote Treg differentiation. However, the precise effect of IL-35 on dendritic cells (DCs) remains to be clarified. Methods: In this study, we investigated the expression of IL-35 in DCs after stimulation with LPS utilizing enzyme linked immunosorbent assay(ELISA), quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) and western blotting, and the influence of IL-35 on the maturation and function of DCs by mixed lymphocyte reaction assay and flow cytometry. We further examined the regulation of IL-35 in DCs by the microRNA let-7i (let-7i) via transfected with let-7i mimic, inhibitor or suppressor of cytokine signalling 1 (SOCS1) siRNA. IL-35-overexpressing DCs were transfused into BALB/c recipients with C57BL/6 heart transplantations to verify the role of immune tolerance in transplantation. Results: The results showed that IL-35 expression was significantly up-regulated following lipopolysaccharide (LPS)-induced DC maturation. Overexpression of IL-35 suppressed DC maturation, promoted the secretion of anti-inflammatory cytokines, and subsequently affected the balance between Treg and Th17 cells. IL-35 expression in DCs was regulated by let-7i, which targets SOCS1. The transfusion of IL-35-transfected DCs induced Treg generation in mice and prolonged cardiac allograft survival. Conclusion: Our data demonstrated that IL-35 induces tolerogenic DCs which are capable of alleviating allograft rejection. Clinical application of IL-35-treated DCs might be a promising approach for eliciting cardiac allograft immune tolerance.