Kirenol Attenuates Experimental Autoimmune Encephalomyelitis by Inhibiting Differentiation of Th1 and Th17 Cells and Inducing Apoptosis of Effector T Cells

Abstract

Experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), is characterized by CNS demyelination mediated by autoreactive T cells. Kirenol, a biologically active substance isolated from Herba Siegesbeckiae, has potent anti-inflammatory activities. Here we investigated effects of kirenol on EAE. Kirenol treatment markedly delayed onset of disease and reduced clinical scores in EAE mice. Kirenol treatment reduced expression of IFN-γ and IL-17A in the serum and proportion of Th1 and Th17 cells in draining lymph nodes. Priming of lymphocytes was reduced and apoptosis of MOG-activated CD4+ T cells was increased in kirenol treated EAE mice. Kirenol treatment of healthy animals did not affect the lymphocytes in these non-immunized mice. Further in vitro studies showed that kirenol inhibited viability of MOG-specific lymphocytes and induced apoptosis of MOG-specific CD4+ T cells in a dose- and time-dependent manner. Kirenol treatment upregulated Bax,downregulated Bcl-2,and increased activation of caspase-3 and release of cytochrome c, indicating that a mitochondrial pathway was involved in kirenol induced apoptosis. Moreover, pretreatment with either a pan-caspase inhibitor z-VAD-fmk or a more specific caspase 3 inhibitor Ac-DEVD-CHO in lymphocytes reduced kirenol induced apoptosis. Our findings implicate kirenol as a useful agent for the treatment of MS.

Rotenone Treatment Reveals a Role for Electron Transport Complex I in the Subcellular Localization of Key Transcriptional Regulators During T Helper Cell Differentiation

“…Studies have highlighted how metabolic pathways are selectively utilized during Th cell differentiation ( 31 , 32 ). Teff cells rely on glucose as their main energy source, while iTregs will oxidize fatty acids to produce the energy they need.…”

Kirenol regulates the cell proliferative and inflammatory markers in DMBA‐induced oral squamous cell carcinogenesis in hamster

“…It has a broad range of pharmaceutical effects immunomodulatory activities. Xiao et al 6 explained kirenol is a natural active substance which delays the onset of diseases and inhibited clinical sources in mice model. Further, their experiments found that kirenol suppressed the viability of specific lymphatic cells and dose dependent induction of cell death through apoptotic marker expressions (Bcl‐2, Bax, caspase‐3, and Cyt‐c) in mitochondrial mediated pathways literature studies showed that kirenol working on various inflammatory responses.…”

Shikonin ameliorates experimental autoimmune encephalomyelitis (EAE) via immunomodulatory, anti-apoptotic and antioxidative activity

“…There are controversial studies about the mechanism of apoptosis in the progression course of EAE. [12][13][14] Cytotoxic immunosuppressants are often used for the treatment of MS patients, in whom the immunemodulatory therapies fail. [15] Cyclophosphamide and azathioprine are traditionally used for the treatment of MS; however, mitoxantrone has been reported to slow the progression and reduce the relapse rate in the disease.…”