527 Uncovering molecular mechanisms involved in the IL-37-mediated tolerogenic dendritic cells

Abstract

The past few years have witnessed a breakthrough in the development of tolerogenic dendritic cell (DC) based therapies for the treatment of autoimmune diseases and solid organ transplantation. The interleukin-1 family member IL-37 is a natural suppressor of innate inflammatory and immune responses. Using mice expressing human IL-37b isoform (IL-37tg), we have previously reported that IL-37 participates in peripheral tolerance through the generation of semi-mature tolerogenic DCs. However, the molecular mechanism(s) and/or regulatory molecule(s) involved in the IL-37-mediated tolerogenic DCs are yet to be identified. Similar to IL-1a and IL-33, IL-37 has a unique property as an intracrine cytokine, functioning both intracellularly and extracellularly. To investigate extracellular mechanisms, recombinant IL-37 and neutralizing antibody to IL-37 were used. Despite their effects on IL-1β secretion, neither recombinant IL-37 nor neutralizing antibody affected the ability of DCs to activate T cell proliferation or induce regulatory T cells, suggesting that extracellular IL-37 has limited effects on DC function. Next, to understand molecular pathways altered by IL-37 in DCs, RNAs from wild-type (WT) and IL-37tg DCs were subjected for Illumina microarray analysis. GeneGo pathway analysis identified a key transcription factor NF-κB and 3 pathways including IL-10, CD40, antigen presentation pathway and HMGB1 pathways. Several differentially expressed genes were identified and verified including CXCL1, IL-10 and others. miRNA array analysis using Nanostring miRNA array kit identified immunosuppressive miRNAs. Furthermore, THP-1 human cell line transfected with IL-37 expressed similar molecular profiles to IL-37 mouse DCs and exhibited lower ability to stimulate proliferation of allogeneic naïve T cells after differentiation into DCs. Together, these findings reveal an immunosuppressive molecular pathways of DCs expressing IL-37.