LF15-0195 generates tolerogenic dendritic cells by suppression of NF-κB signaling through inhibition of IKK activity

Journal of Leukocyte Biology

Gill H. Strejan²  David J. White³  Xiaoping Xia²  Mu Li⁴  Dejun Zhou²  Xuyan Huang⁴  Robert Zhong¹  Thomas E. Ichim²  Wei-Ping Min⁶  Jinming Yang²  Suzanne M. Bernier⁵ 

[1] Surgery, Medicine, Pathology, Microbiology and Immunology, and The John P. Robarts Research Institute, London, Canada; Multi-Organ Transplant Program, London Health Sciences Centre, Canada; and Immunology and Transplantation, Lawson Health Research Institute, London, Canada Surgery, Medicine, Pathology, Microbiology and Immunology, and Surgery, Medicine, Pathology, Microbiology and Immunology, and The John P. Robarts Research Institute, London, Canada; Multi-Organ Transplant Program, London Health Sciences Centre, Canada; and Immunology and Transplantation, Lawson Health Research Institute, London, Canada The John P. Robarts Research Institute, London, Canada; Surgery, Medicine, Pathology, Microbiology and Immunology, and The John P. Robarts Research Institute, London, Canada; Multi-Organ Transplant Program, London Health Sciences Centre, Canada; and Immunology and Transplantation, Lawson Health Research Institute, London, Canada Multi-Organ Transplant Program, London Health Sciences Centre, Canada; and Surgery, Medicine, Pathology, Microbiology and Immunology, and The John P. Robarts Research Institute, London, Canada; Multi-Organ Transplant Program, London Health Sciences Centre, Canada; and Immunology and Transplantation, Lawson Health Research Institute, London, Canada Immunology and Transplantation, Lawson Health Research Institute, London, Canada Surgery, Medicine, Pathology, Microbiology and Immunology, and The John P. Robarts Research Institute, London, Canada; Multi-Organ Transplant Program, London Health Sciences Centre, Canada; and Immunology and Transplantation, Lawson Health Research Institute, London, Canada;Surgery, Medicine, Pathology, Microbiology and Immunology, and Surgery, Medicine, Pathology, Microbiology and Immunology, and Surgery, Medicine, Pathology, Microbiology and Immunology, and;Surgery, Medicine, Pathology, Microbiology and Immunology, and The John P. Robarts Research Institute, London, Canada; Multi-Organ Transplant Program, London Health Sciences Centre, Canada; and Surgery, Medicine, Pathology, Microbiology and Immunology, and Surgery, Medicine, Pathology, Microbiology and Immunology, and The John P. Robarts Research Institute, London, Canada; Multi-Organ Transplant Program, London Health Sciences Centre, Canada; and The John P. Robarts Research Institute, London, Canada; Surgery, Medicine, Pathology, Microbiology and Immunology, and The John P. Robarts Research Institute, London, Canada; Multi-Organ Transplant Program, London Health Sciences Centre, Canada; and Multi-Organ Transplant Program, London Health Sciences Centre, Canada; and Surgery, Medicine, Pathology, Microbiology and Immunology, and The John P. Robarts Research Institute, London, Canada; Multi-Organ Transplant Program, London Health Sciences Centre, Canada; andSurgery, Medicine, Pathology, Microbiology and Immunology, and The John P. Robarts Research Institute, London, Canada; Surgery, Medicine, Pathology, Microbiology and Immunology, and Surgery, Medicine, Pathology, Microbiology and Immunology, and The John P. Robarts Research Institute, London, Canada; The John P. Robarts Research Institute, London, Canada; Surgery, Medicine, Pathology, Microbiology and Immunology, and The John P. Robarts Research Institute, London, Canada;Anatomy and Cell Biology, CIHR Group in Skeletal Development and Remodeling, University of Western Ontario, London, Canada; Anatomy and Cell Biology, CIHR Group in Skeletal Development and Remodeling, University of Western Ontario, London, Canada; Anatomy and Cell Biology, CIHR Group in Skeletal Development and Remodeling, University of Western Ontario, London, Canada;;Surgery, Medicine, Pathology, Microbiology and Immunology, and Multi-Organ Transplant Program, London Health Sciences Centre, Canada; and Immunology and Transplantation, Lawson Health Research Institute, London, Canada Surgery, Medicine, Pathology, Microbiology and Immunology, and Surgery, Medicine, Pathology, Microbiology and Immunology, and Multi-Organ Transplant Program, London Health Sciences Centre, Canada; and Immunology and Transplantation, Lawson Health Research Institute, London, Canada Multi-Organ Transplant Program, London Health Sciences Centre, Canada; and Surgery, Medicine, Pathology, Microbiology and Immunology, and Multi-Organ Transplant Program, London Health Sciences Centre, Canada; and Immunology and Transplantation, Lawson Health Research Institute, London, Canada Immunology and Transplantation, Lawson Health Research Institute, London, Canada Surgery, Medicine, Pathology, Microbiology and Immunology, and Multi-Organ Transplant Program, London Health Sciences Centre, Canada; and Immunology and Transplantation, Lawson Health Research Institute, London, Canada

关键词: transplantation tolerance;    immune modulation;    cytokines;   

DOI  :  10.1189/jlb.1102582

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

LF15-0195 (LF) is a potent, less toxic analog of the immunosuppressant 15-deoxyspergualine, which we previously reported to prevent graft rejection and to induce permanent tolerance in a murine cardiac transplantation model. However, the underlying mechanism of action of LF required elucidation. In this study, dendritic cells (DC) treated with LF before activation with tumor necrosis factor α (TNF-α)/lipopolysaccharide (LPS) failed to express maturation markers (major histocompatibility complex II, CD40, CD86) and interleukin-12. LF prevented, in a concentration-dependent manner, the activation and nuclear translocation of nuclear factor-κB (NF-κB) in DC following addition of TNF-α/LPS. Yet-activated and active IκB kinases (IKKs) were inhibited in cells pretreated with LF, thereby preventing the phosphorylation of IκB and release of NF-κB, a key regulator of genes associated with the maturation of DC. LF-induced inhibition of IKK activity was reversed in a dose-dependent manner by the overexpression of IKK. The T helper cell type 2 (Th2) differentiation of naïve T cells promoted by LF-treated DC in vitro correlates with Th2 polarization observed in transplant recipients made tolerant by LF. These data demonstrated that LF-induced blockade of NF-κB signaling at the level of IKK promoted the generation of tolerogenic DC that inhibited Th1 polarization and increased Th2 polarization in vitro and in vivo.

【 授权许可】

Unknown