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Published online before print July 15, 2003

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(Journal of Leukocyte Biology. 2003;74:438-447.)
© 2003 by Society for Leukocyte Biology

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

Jinming Yang^*, Suzanne M. Bernier, Thomas E. Ichim^*, Mu Li^*,, Xiaoping Xia^*, Dejun Zhou^*, Xuyan Huang^*,, Gill H. Strejan^*, David J. White^*,,, Robert Zhong^*,,,¶ and Wei-Ping Min^*,,¶,1

Departments of
^* Surgery, Medicine, Pathology, Microbiology and Immunology, and
Anatomy and Cell Biology, CIHR Group in Skeletal Development and Remodeling, University of Western Ontario, London, Canada;
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

¹Correspondence: 339 Windermere Road, LHSC-UC 9L9, London, Ontario, N6A 5A5, Canada. E-mail: mweiping{at}uwo.ca

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 (TNF-)/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-B (NF-B) in DC following addition of TNF-/LPS. Yet-activated and active IB kinases (IKKs) were inhibited in cells pretreated with LF, thereby preventing the phosphorylation of IB and release of NF-B, 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-B 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.

Key Words: transplantation tolerance • immune modulation • cytokines

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