Introduction
Autoimmune hepatitis (AIH) is a chronic self-perpetuating liver
inflammatory disease that affects all ages, both genders, and all
ethnicities (Mack et al. , 2019).
AIH may start with an episode of acute hepatitis and eventually lead to
liver cirrhosis, liver cancer, the need for liver transplantation, or
death (Manns et al. , 2015). The
precise etiology of AIH is unknown, but it is been widely believed that
natural killer T (NKT) cells and conventional T cells contribute to
AIH-induced liver damage (Mattner, 2013;
Mieli-Vergani et al. , 2018). The
prominent features of these two cell populations during AIH include an
accumulation in the liver, aberrant activation, and imbalanced Th1/Th2
responses (Senaldi et al. , 1992;
Santodomingo-Garzon et al. , 2011).
Once a T cell-mediated autoimmune response is initiated, hepatocytes can
potentially be destroyed directly through Fas/Fas ligand (FasL)
interactions and/or the action of TNF-α and perforins/granzyme B, or
indirectly through the release of Th1-biased IFN-γ
(Mieli-Vergani et al. , 2018).
Therefore, T cells are expected to be the therapeutic targets in the
treatment of AIH.
The mainstay of treatment for AIH is immunosuppression
(Vergani et al. , 2012).
Concanavalin A (Con A)-induced acute hepatitis in mice is considered to
be a well-characterized model for studying the pathogenesis of AIH and
screening immunosuppressive agents (Tiegset al. , 1992). Con A primarily stimulates the recruitment and
activation of NKT and conventional T cells, coinciding with the
generation of large amounts of proinflammatory Th1 cytokines
(Heymann et al. , 2015). In recent
years, based on the administration of Con A to model animals, many new
therapeutic drugs, antibodies, and proteins have been developed to
attenuate liver injury by inhibiting NKT/T cell activation and skewing
(Wang et al. , 2012).
Fungus-derived natural products and their derivatives, such as
cyclosporine and mycophenolate mofetil, are widely used in the treatment
of autoimmune diseases (Lee et al. ,
2008; Fakih et al. , 2018).
Preparations of fungi and their metabolites have a low synthetic cost,
high practical value, and broad application in medicine, thanks to their
wide availability and high biological activity
(Sharma et al. , 2016). In a
previous screening of anti-inflammatory agents, we found that
secoemestrin C (Fig. 1A), isolated from Aspergillus nidulans , had
a potent inhibitory effect on Con A-induced splenocyte proliferation,
suggesting potential immunosuppressive and anti-inflammatory activity.
In the present study, we sought to investigate whether secoemestrin C
could protect against Con A-induced autoimmune hepatitis in mice and to
explore potential mechanisms for such an effect.