An acidic polysaccharide of Panax ginseng ameliorates experimental autoimmune encephalomyelitis and induces regulatory T cells
Highlights
► APG, an acidic polysaccharide of Panax ginseng. ► APG regulates inflammatory and encephalitogenic response in experimental autoimmune encephalomyelitis (EAE). ► APG induces clinically beneficial effects for its therapeutic immunosuppression of EAE.
Introduction
Experimental autoimmune encephalomyelitis (EAE) is an inflammatory and demyelinating autoimmmune model of diseases in the central nervous system (CNS). EAE bears pathologic and clinical similarities to human multiple sclerosis (MS) and is used as a model to test potential therapeutic agents [1]. The objective of such therapies is to control autoreactive T cell responses and to maintain peripheral self-tolerance via immunosuppressive activities [2], [3], [4]. Recently, the alteration or reduction of CD4+CD25+ regulatory T cell (Treg) functions has been reported in patients with MS and other autoimmune diseases [5], [6]. Tregs contribute to the maintenance of peripheral tolerance and active suppression of autoimmunity in a T cell receptor (TCR)-dependent manner, as established when their depletion increased the severity of and mortality from EAE [7]. However, the endogenous factors and mechanisms controlling the peripheral expansion of Tregs are mostly unknown.
The agent commonly called ginsan is a purified acidic polysaccharide extracted from the roots of Panax ginseng (APG) [8]. APG stimulates normal lymphoid cells to proliferate and to produce cytokines such as interleukin (IL)-1, IL-2, interferon (IFN)-γ and granulocyte monocyte colony-stimulating factor (GM-CSF) [8], [9]. In addition, APG significantly reduces the production of inflammatory cytokines such as tumor necrosis factor (TNF)-α, IL-1β, IL-6, IFN-γ, IL-12, and IL-18 at the early phase of sepsis in mice [10]. The inflammatory response diminished by APG treatment for sepsis as a consequence of down-regulated signals that were transmitted through Toll-like receptors (TLRs) [10]. TLRs trigger intracellular signaling pathways resulting in the regulation of inflammatory cytokines that promote Th1 or Th17 responses [11], [12], [13]. Moreover, TLR agonists can be used to break immunological tolerance and induce Th1-mediated autoimmune diseases such as arthritis [14], EAE [15], and diabetes [16].
Therefore, we hypothesized that APG may have clinically beneficial effects on EAE through the reduction of inflammatory cytokine production. Our data demonstrate that APG significantly reduces the severity of EAE by inhibiting the proliferation of autoreactive T cells as well as production of the inflammatory cytokines, IFN-γ, IL-1β and IL-17. We further demonstrate that APG treatment significantly boosts the expression of Foxp3 in the CNS of APG-treated mice during EAE. Moreover, depletion of CD25+ cells abrogates the beneficial effects of APG treatment in mice with EAE. These observations provide a powerful rationale for more thoroughly assessing the efficacy of APG as a novel therapeutic approach to the treatment of MS.
Section snippets
Animals
C57BL/6 female mice were purchased from Orientbio, Inc. (Sungnam, Korea) and were 6–8 weeks old and weighed 18–25 g when used for the experiments. These mice were housed in conventional animal facilities with a NIH-07-approved diet and water ad libitum at a constant temperature (23 ± 1 °C) according to the guidelines for the Care and Use of Laboratory Animals of the Institutional Ethical Committee of Jeju National University.
Antigens and antibodies
Synthetic murine myelin oligodendrocyte glycoprotein (MOG)35–55 peptide
APG induced resistance to EAE
To study the effect of APG on the development of EAE, we immunized PBS- or APG-treated EAE mice with MOG35–55 peptide and monitored them for signs of EAE for 33 days post-immunization. As Fig. 1 depicts, APG effectively reduced the severity of EAE. In PBS-treated mice, EAE developed by day 9 after immunization and reached a maximal clinical score of 2.5 ± 0.08 two weeks later. By contrast, the APG-treated group had a delayed onset of symptoms (day 12) and far less severe disease, reaching a
Discussion
Recently, Tregs have been reported to play a critical role in controlling autoimmune diseases, including MS [5], [6]. Kohm et al. [17] have reported that Tregs from conventional C57BL/6 mice suppress active and passive EAE associated with a decrease of autoreactive Th1 cells and that Tregs inhibit both the proliferation and IFN-γ production by a MOG35–55-specific Th1 cell line in vitro. This notion is supported by our results demonstrating that APG significantly reduced the disease severity of
Acknowledgement
This research was performed under a program of the Korea Research Foundation of the Korean Government (MOEHRD) (KRF-2006-E00366).
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