Year of Award

2007

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Pharmaceutical Sciences

Other Degree Name/Area of Focus

Pharmacology

Department or School/College

College of Health Professions and Biomedical Sciences

Committee Chair

David M. Shepherd

Committee Co-chair

Jerry R. Smith

Commitee Members

Keith K. Parker, John M. Gerdes, Sarah J. Miller

Keywords

Antigen Presenting Cells, Dendritic Cells, immune system, Macrophages, Toll-like receptors Panax notoginseng

Abstract

Antigen presenting cells (APCs) perform the essential task of integrating responses between the innate and adaptive immune system. Several approaches have been undertaken to manipulate the effects of APCs for therapeutic purposes. Panax notoginseng is a medicinal herb that is purported to possess a number of properties including modulation of the immune system. However, limited information exists on the effects and toxicities of this herbal on APCs. In this regard, we assessed the effects of Panax notoginseng on the fate and function of professional APCs in murine models using macrophages and dendritic cells (DCs). APCs were stimulated with the toll-like receptor ligands LPS, CpG and poly(I:C) and treated with notoginseng (0-200 ìg/ml). The LPS induced levels of the proinflammatory cytokine TNF-á, as well as the expression of accessory molecules MHC II, CD40 and CD86, were decreased dependent on notoginseng exposure time-points relative to LPS stimulation. LPS induced IL-1â, IL-6 and IL-12 production was also decreased with concurrent notoginseng treatment for 24 hours. Notoginseng decreased TNF-á and CD40 activation by CpG and poly(I:C), but had varied effects on the induction of IL-6 and CD86. Furthermore, treatment of APCs with ginsenosides Rb1 and Rg1 had differential effects on the production of TNF-á and IL-6. Phagocytosis of FITC-conjugated ovalbumin antigen by DCs was decreased by notoginseng. Furthermore, the uptake of FITC-conjugated modified LDL was reduced in notoginseng treated DCs. However, T cell proliferation in response to notoginseng treated-antigen-loaded DCs was not affected in vitro or in vivo. Mechanistically, notoginseng reduced nuclear levels of the transcription factor NFêB, but had no effect on glucocorticoid receptor activation. No immunotoxicities were observed with low dose notoginseng (660 ìg/kg) treatment of Balb/c mice in vivo. Collectively, our results indicate that notoginseng decreased inflammatory mediator production by APCs, without altering their ability to induce antigen specific CD 4+ T cell proliferation. Our research provides insight into the potential use of this herbal in the treatment of inflammatory diseases as a safe and effective complement to existing remedies.

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© Copyright 2007 Ava-Gaye Tania Rhule