Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.0708441 on June 4, 2009

Published online before print June 4, 2009
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(Journal of Leukocyte Biology. 2009;86:877-889.)
© 2009 Society for Leukocyte Biology

An immunomodulatory protein, Ling Zhi-8, induced activation and maturation of human monocyte-derived dendritic cells by the NF-{kappa}B and MAPK pathways

Yu-Li Lin*,{dagger}, Yu-Chih Liang{ddagger}, Yu-Shan Tseng{dagger}, Hsin-Yi Huang{dagger}, Shu-Yu Chou§, Ruey-Shyang Hseu§, Ching-Tsan Huang§ and Bor-Luen Chiang*,{dagger},1

* Department of Medical Research,
{dagger} Graduate Institute of Clinical Medicine, College of Medicine, and
§ Department of Biochemical Science and Technology, Institute of Microbiology and Biochemistry, National Taiwan University, Taipei, Taiwan, Republic of China; and
{ddagger} Graduate Institute of Biomedical Technology, College of Medicine, Taipei Medical University, Taipei, Taiwan, Republic of China

1. Correspondence: Department of Pediatrics, National Taiwan University Hospital, No. 7, Chungshan South Road, Taipei, Taiwan, R.O.C. E-mail: gicmbor{at}ntu.edu.tw

ABSTRACT

Ganoderma lucidum, an oriental medicinal mushroom, has been widely used in Asia to promote health and longevity. LZ-8 is a protein derived from the fungus G. lucidum and has immunomodulatory capacities. In this study, we investigated the immune modulatory effects of rLZ-8 on human monocyte-derived DCs. Treatment of DC with rLZ-8 resulted in the enhanced cell-surface expression of CD80, CD86, CD83, and HLA-DR, as well as the enhanced production of IL-12 p40, IL-10, and IL-23, and the capacity for endocytosis was suppressed in DCs. In addition, treatment of DCs with rLZ-8 resulted in an enhanced, naïve T cell-stimulatory capacity and increased, naïve T cell secretion of IFN-{gamma} and IL-10. Neutralization with antibodies against TLR4 inhibited the rLZ-8-induced production of IL-12 p40 and IL-10 in DCs. rLZ-8 can stimulate TLR4 or TLR4/MD2-transfected HEK293 cells to produce IL-8. These results suggested an important role for TLR4 in signaling DCs upon incubation with rLZ-8. Further study showed that rLZ-8 was able to augment IKK, NF-{kappa}B activity, and also I{kappa}B{alpha} and MAPK phosphorylation. Further, inhibition of NF-{kappa}B by helenalin prevented the effects of rLZ-8 in the expression of CD80, CD86, CD83, and HLA-DR and production of IL-12 p40 and IL-10 in various degrees. To confirm the in vitro data, we investigated the effect of rLZ-8 further on antigen-specific antibody and cytokine production in BALB/c mice. Immunization with OVA/rLZ-8 showed that the anti-OVA IgG2a, IFN-{gamma}, and IL-2 were increased significantly compared with OVA alone in BALB/c mice. In conclusion, our experiments demonstrated that rLZ-8 can effectively promote the activation and maturation of immature DCs, preferring a Th1 response, suggesting that rLZ-8 may possess a potential effect in regulating immune responses.

Key Words: dendritic cells • cytokine • LZ-8 • T cells • signal transduction