Ethnopharmacological communicationGlabretal-type triterpenoid from the root bark of Dictamnus dasycarpus ameliorates collagen-induced arthritis by inhibiting Erk-dependent lymphocyte proliferation
Graphical abstract
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.
References (17)
- et al.
Antiproliferative glabretal-type triterpenoids from the root bark of Dictamnus dasycarpus
Bioorg. Med. Chem. Lett.
(2015) - et al.
Composition, cytotoxicity and antimicrobial activity of essential oil from Dictamnus dasycarpus
Food Chem.
(2008) - et al.
Mitogen-activated protein kinase/ERK kinase kinases 2 and 3 activate nuclear factor-κB through IκB kinase-α and IκB kinase-β
J. Biol. Chem.
(1999) - et al.
Defective TCR expression in transgenic mice constructed using cDNA-based &agr;-and &bgr;-chain genes under the control of heterologous regulatory elements
Immunol. Cell. Biol.
(1998) - et al.
Emerging cell and cytokine targets in rheumatoid arthritis
Nat. Rev. Rheumatol.
(2014) - et al.
Seven new sesquiterpene glycosides from the root bark of Dictamnus dasycarpus
J. Nat. Prod.
(2001) - et al.
Expression pattern and functional role of Phc2 during activation of helper T cells after antigenic stimulation
Vitr. Cell. Dev–.
(2013) - et al.
The molecular role of Myc in growth and transformation: recent discoveries lead to new insights
FASEB J.
(1998)