Premium
LF15‐0195 generates tolerogenic dendritic cells by suppression of NF‐κB signaling through inhibition of IKK activity
Author(s) -
Yang Jinming,
Bernier Suzanne M.,
Ichim Thomas E.,
Li Mu,
Xia Xiaoping,
Zhou Dejun,
Huang Xuyan,
Strejan Gill H.,
White David J.,
Zhong Robert,
Min WeiPing
Publication year - 2003
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.1102582
Subject(s) - biology , tumor necrosis factor alpha , cd40 , cd86 , lipopolysaccharide , microbiology and biotechnology , iκb kinase , kinase , phosphorylation , signal transduction , immunology , cancer research , in vitro , nf κb , t cell , immune system , cytotoxic t cell , biochemistry
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.