1. Introduction
Allergic rhinitis (AR) is an allergic inflammation of the nasal airways
and is characterized by sneezing, rhinorrhea, itching, and nasal
congestion. These clinical conditions are widely known to be induced by
inflammatory mediators, including histamine, leukotrienes, and
inflammatory cytokines, which are secreted by eosinophils (Pawankar,
Mori, Ozu, & Kimura, 2011). AR is one of the world’s most common
chronic illnesses among children and young adults, and its prevalence is
estimated to range from approximately 10–50% (Bellanti & Wallerstedt,
2000). Anti-allergic and anti-histamine agents are commonly used in the
treatment of allergic rhinitis; however, their effects are transient as
they are only able to suppress the symptoms of the inflammatory response
(Adamia, Jorjoliani, Khachapuridze, Katamadze, & Chkuaseli, 2015).
Therefore, it is important to develop novel therapeutic strategies that
are effective for the treatment of AR (Mowen & Glimcher, 2004). A T-box
protein expressed in T cells (T‐bet) is a transcription factor
specifically expressed in Type 1 helper T (Th1) cells. GATA-3, on the
other hand, has been shown to be an important factor in mediating
allergic airway inflammation in vivo (Zhang et al., 1999). Effective
therapeutic strategies would aim to either downregulate Th2 or Th17
cytokines or to downregulate the transcription factors that inhibit
their production. Retinoic acid-related orphan nuclear receptor (ROR) γt
is a splice variant of ROR, which has been identified as an essential
transcription factor during Th17 cellular differentiation (Chen et al.,
2011).
Patients with AR show an inflammatory Immunoglobulin E (IgE)-mediated
response characterized by the Th2 immunological pattern together with
mast cells, goblet cells, and eosinophil activation, as well as the
release of inflammatory mediators, such as interleukin (IL)-4 and IL-5,
against allergen exposure (Durham et al., 1992). Th1/Th2 cells are
associated with a series of immune and inflammatory diseases, such as
bacterial and viral infectious diseases (Meagher, Wines, & Cooper,
2002; Walker, Virchow, Bruijnzeel, & Blaser, 1991). To date, the
discovery of Th17 cells has introduced complexity into the existing
Th1/Th2 balance paradigm and expanded our understanding of the
pathogenesis of AR (S. B. Wang et al., 2014). Th17 cells are newly
emerged immune/inflammatory cell subsets, which are now widely believed
to be critical for the regulation of various chronic immune diseases
(Halwani, Al-Muhsen, & Hamid, 2013). Th17 cells enhance eosinophilic
airway inflammation, which is mediated by Th2 cells (Wakashin et al.,
2008). Nuclear factor-kappa B (NF-κB) is a multicellular transcription
factor, and it plays an important role in inflammatory and immune
responses by regulating the gene expression of immune and
inflammation-related cytokines and inflammatory mediators, which is a
vital role in the initiation and perpetuation of allergic inflammation
(Kumar, Takada, Boriek, & Aggarwal, 2004; Wan & Lenardo, 2010). The
transcription factor T-bet drives Th1 differentiation, while the
transcription factor GATA-3 drives Th2 differentiation.
Natural products are regarded as abundant sources of novel drug
candidates, and their pharmacological usefulness has been proven through
decades of research (Newman & Cragg, 2016). In addition, drugs derived
from natural products are known to induce fewer side effects than many
synthetic drugs (Mathur & Hoskins, 2017). Saikosaponin D (SSD, chemical
structure shown in Fig. 1A), one of the triterpenoid saponins derived
from Bupleurum falcatum L, is a commonly prescribed agent against
inflammatory diseases in China, Japan, and other Asian countries (Lu et
al., 2012; Wong et al., 2013). Several studies have shown that SSD has
anti-inflammatory, immunomodulatory, antiviral, and anticancer
activities (H. W. Wang, Liu, Zhong, & Fang, 2015). Other researchers
have found that SSD exhibited an anti-proliferative effect on the
activated T lymphocyte via suppression of the NF-κB, NF-AT, and AP-1
signaling pathways (Sun, Cai, Zhou, & Xu, 2009; Wong et al., 2013).
However, the mechanism underlying the anti-allergic effect of SSD on
allergic rhinitis remains unclear. In the current study, we explore the
protective effects and therapeutic efficacy of SSD on an ovalbumin
(OVA)-induced AR mice model, which potentially involves the regulation
of the Th1/Th2 and Th17 cellular responses.