Elsevier

Journal of Ethnopharmacology

Volume 178, 3 February 2016, Pages 13-16
Journal of Ethnopharmacology

Ethnopharmacological communication
Glabretal-type triterpenoid from the root bark of Dictamnus dasycarpus ameliorates collagen-induced arthritis by inhibiting Erk-dependent lymphocyte proliferation

https://doi.org/10.1016/j.jep.2015.10.043Get rights and content

Abstract

Ethnopharmacological relevance

The root bark of Dictamnus dasycarpus Turcz. (Rutaceae) has been used as a traditional herbal medicine to treat various inflammatory diseases in East Asia. We have showed previously that a glabretal type triterpenoid (dictabretol A) from D. dasycarpus root bark has immunosuppressive activity.

Aim of the study

This study was conducted to define the molecular mechanism of how dictabretol A inhibits lymphocyte proliferation and to evaluate the therapeutic efficacy of dictabretol A in an animal model of rheumatoid arthritis.

Materials and methods

Various murine immune cells (T cells, B cells, and macrophages) and splenocytes were used to study the anti-proliferative effect of dictabretol A in vitro. A collagen-induced arthritis model was also used to examine the therapeutic effect of dictabretol A in vivo.

Results

Dictabretol A specifically inhibited lymphocyte proliferation by blocking the cell cycle transition from the G1 to the S phase. This effect was achieved by blocking Erk1/2, nuclear factor kappa B, and the C-myc axis of cell cycle progression. Further dictabretol A treatment alleviated the severity of collagen-induced arthritis.

Conclusion

Our results reveal the molecular mechanism for the anti-lymphoproliferative effect of dictabretol A and show the therapeutic efficacy of dictabretol A for rheumatoid arthritis.

Introduction

Immunity is a complex and sophisticated network that orchestrates various subsets of immune cells. Both innate and adaptive immunity interact to protect the body against threats from foreign antigens, which are mainly associated with microbial pathogens. However, an excess immune response or activation of lymphocytes by self-antigens causes hypersensitivity or autoimmune disease that destroys specific tissues or cells (Ganguly et al., 2013, Wu and Zarrin, 2014). Also, inappropriate immune responses cause graft rejection when a MHC mismatched organ is transplanted to a recipient (Wood and Goto, 2012). Therefore, immunosuppressive agents are necessary to control immune homeostasis in patients with immune-related diseases.

The root bark of Dictamnus dasycarpus Turcz. (Rutaceae) have been widely used as an herbal medicine for the treatment of cough, jaundice, rheumatism, and skin inflammation in East Asia (Chang et al., 2001, Lei et al., 2008, Wu, 2005). We showed previously that a glabretal type triterpenoid (dictabretol A) from this plant has anti-proliferative activity against immune cells (Kim et al., 2015). In this study, we defined the anti-lymphoproliferative mechanism of dictabretol A and investigated the effect of dictabretol A on disease progression in a collagen-induced arthritis (CIA) model to evaluate the potency of dictabretol A as a novel immunosuppressive agent.

Section snippets

Antibodies and reagents

See the Materials and Methods section of Supplementary Material for the details on the antibodies and reagents.

Dictabretol A purification

The dried root bark of D. dasycarpus was purchased from Kyung Dong market, Seoul, Korea, in January 2008, and was authenticated by Emeritus Professor Kyong Soon Lee, College of Pharmacy, Chungbuk National University, Cheongju, Korea. A voucher specimen (no. SS45-01142008) was deposited at the College of Life Sciences and Biotechnology, Korea University, Seoul, Korea. Dictabretol A was

Dictabretol A induces cell cycle arrest from the G1 phase to S phase transition in lymphocytes through Erk1/2 pathway

The molecular formula of dictabretol A is C35H56O7 with eight degrees of unsaturation (Fig. 1A). No significant cell death was observed in splenocytes and cell lines (RMA, A20 and J774 cells) treated with up to 2 μM of dictabretol A (Supplementary Fig. S1). Next, we performed CFSE labeling assay as an in vitro model system for cell proliferation, showing that dictabretol A (2 µM) treatment effectively inhibits both T and B cell proliferation when compared to those of untreated cells or 0.1% DMSO

Conclusion

This study defined the molecular mechanism of how dictabretol A has anti-lymphoproliferative effects and demonstrated the therapeutic efficacy of dictabretol A in a rheumatoid arthritis model. Dictabretol A specifically blocked the cell cycle transition from the G1 phase to the S phase by inhibiting Erk-dependent signaling and may be a candidate novel therapeutic agent to treat chronic inflammatory disease.

Acknowledgments

This work was supported by Bio-industry Technology Development Program (No. 114065-3), Ministry of Agriculture, Food and Rural Affairs, Republic of Korea.

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