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Eriocalyxin B ameliorates experimental autoimmune encephalomyelitis by suppressing Th1 and Th17 cells.

ABSTRACT: Eriocalyxin B (EriB), a diterpenoid isolated from Isodon eriocalyx, was previously reported to have antitumor effects via multiple pathways, and these pathways are related to immune responses. In this study, we demonstrated that EriB was efficacious in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Treatment with EriB led to amelioration of EAE, which correlated with reduced spinal cord inflammation and demyelination. EriB treatment abolished encephalitogenic T-cell responses to myelin oligodendrocyte glycoprotein in an adoptive transfer EAE model. The underlying mechanism of EriB-induced effects involved inhibition of T helper (Th) 1 and Th17 cell differentiation through Janus Kinase/Signal Transducer and Activator Of Transcription and Nuclear factor-?B signaling pathways as well as elevation of reactive oxygen species. These findings indicate that EriB exerts potent antiinflammatory effects through selective modulation of pathogenic Th1 and Th17 cells by targeting critical signaling pathways. The study provides insights into the role of EriB as a unique therapeutic agent for the treatment of autoimmune diseases.

SUBMITTER: Lu Y

PROVIDER: S-EPMC3568304 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Eriocalyxin B ameliorates experimental autoimmune encephalomyelitis by suppressing Th1 and Th17 cells.

Lu Ying Y Chen Bing B Song Jun-Hong JH Zhen Tao T Wang Bai-Yan BY Li Xin X Liu Ping P Yang Xin X Zhang Qun-Ling QL Xi Xiao-Dong XD Chen Sheng-Di SD Zuo Jian-Ping JP Chen Zhu Z Chen Sai-Juan SJ

Proceedings of the National Academy of Sciences of the United States of America 20130123 6

Eriocalyxin B (EriB), a diterpenoid isolated from Isodon eriocalyx, was previously reported to have antitumor effects via multiple pathways, and these pathways are related to immune responses. In this study, we demonstrated that EriB was efficacious in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Treatment with EriB led to amelioration of EAE, which correlated with reduced spinal cord inflammation and demyelination. EriB treatment abolished encephalito ...[more]

PMID: 23345445

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Project description:BackgroundThere is consensus that experimental autoimmune encephalomyelitis (EAE) can be mediated by myelin specific T cells of Th1 as well as of Th17 phenotype, but the contribution of either subset to the pathogenic process has remained controversial. In this report, we compare functional differences and pathogenic potential of "monoclonal" T cell lines that recognize myelin oligodendrocyte glycoprotein (MOG) with the same transgenic TCR but are distinguished by an IFN-? producing Th1-like and IL-17 producing Th17-like cytokine signature.Methods and findingsCD4+ T cell lines were derived from the transgenic mouse strain 2D2, which expresses a TCR recognizing MOG peptide 35-55 in the context of I-A(b). Adoptive transfer of Th1 cells into lymphopenic (Rag2?/?) recipients, predominantly induced "classic" paralytic EAE, whereas Th17 cells mediated "atypical" ataxic EAE in approximately 50% of the recipient animals. Combination of Th1 and Th17 cells potentiated the encephalitogenicity inducing classical EAE exclusively. Th1 and Th17 mediated EAE lesions differed in their composition but not in their localization within the CNS. While Th1 lesions contained IFN-?, but no IL-17 producing T cells, the T cells in Th17 lesions showed plasticity, substantially converting to IFN-? producing Th1-like cells. Th1 and Th17 cells differed drastically by their lytic potential. Th1 but not Th17 cells lysed autoantigen presenting astrocytes and fibroblasts in vitro in a contact-dependent manner. In contrast, Th17 cells acquired cytotoxic potential only after antigenic stimulation and conversion to IFN-? producing Th1 phenotype.ConclusionsOur data demonstrate that both Th1 and Th17 lineages possess the ability to induce CNS autoimmunity but can function with complementary as well as differential pathogenic mechanisms. We propose that Th17-like cells producing IL-17 are required for the generation of atypical EAE whereas IFN-? producing Th1 cells induce classical EAE.

Project description:Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by infiltrating inflammatory cells and demyelinating lesions, and T helper (Th) cells play critical roles in the pathogenesis of MS. There is still lack of effective treatments currently. Pien Tze Huang (PZH), a traditional Chinese medicine formula, has been proved to have anti-inflammatory, neuroprotective, and immunoregulatory effects. However, whether PZH can be used to treat MS is still obscure. This study aimed to investigate the possible therapeutic effect and the underlying action mechanism of PZH in relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) mice. Female SJL/J mice were immunized with myelin proteolipid protein 139-151 (PLP139-151) and pertussis toxin to establish RR-EAE model. Mice were then randomly divided into normal group, model group, PZH group and positive control group (fingolimod, FTY-720), and drugs were orally administered for 60 days from the day 10 after immunization. Sera of mice were collected for ELISA detection. Tissues of CNS were harvested for hematoxylin-eosin (H-E) and luxol fast blue (LFB) staining. Furthermore, Th1, Th17 cells and their related cytokines in the CNS were detected by flow cytometry and quantitative real-time PCR, respectively. Proteins involved in STAT and NF-κB signaling pathways were detected by western blot. The results showed that PZH-treated mice displayed mild or moderate clinical symptoms compared with untreated EAE mice that exhibited severe clinical symptoms. PZH remarkably reduced inflammatory cell infiltration and myelin damage in the CNS of EAE mice. It markedly down-regulated the levels of IFN-γ and IL-17A in sera of EAE mice. Moreover, PZH could reduce the percentages of Th1 and Th17 cells. It also suppressed the production of transcription factors ROR-γt and T-bet as well as the mRNA levels of their downstream pro-inflammatory cytokines, such as IFN-γ and IL-17A. Furthermore, PZH could inhibit the phosphorylation of some key proteins in the STAT and NF-κB signaling pathways. In conclusion, the study demonstrated that PZH had a therapeutic effect on RR-EAE mice, which was associated with the modulation effect on Th1 and Th17 cells.

Project description:BackgroundMultiple sclerosis (MS) is a progressive autoimmune disease characterized by the accumulation of pathogenic inflammatory immune cells in the central nervous system (CNS) that subsequently causes focal inflammation, demyelination, axonal injury, and neuronal damage. Experimental autoimmune encephalomyelitis (EAE) is a well-established murine model that mimics the key features of MS. Presently, the dietary consumption of foods rich in phenols has been reported to offer numerous health benefits, including anti-inflammatory activity. One such compound, 4-ethylguaiacol (4-EG), found in various foods, is known to attenuate inflammatory immune responses. However, whether 4-EG exerts anti-inflammatory effects on modulating the CNS inflammatory immune responses remains unknown. Thus, in this study, we assessed the therapeutic effect of 4-EG in EAE using both chronic and relapsing-remitting animal models and investigated the immunomodulatory effects of 4-EG on neuroinflammation and Th1/Th17 differentiation in EAE.MethodsChronic C57BL/6 EAE and relapsing-remitting SJL/J EAE were induced followed by 4-EG treatment. The effects of 4-EG on disease progression, peripheral Th1/Th17 differentiation, CNS Th1/Th17 infiltration, microglia (MG) activation, and blood-brain barrier (BBB) disruption in EAE were evaluated. In addition, the expression of MMP9, MMP3, HO-1, and Nrf2 was assessed in the CNS of C57BL/6 EAE mice.ResultsOur results showed that 4-EG not only ameliorated disease severity in C57BL/6 chronic EAE but also mitigated disease progression in SJL/J relapsing-remitting EAE. Further investigations of the cellular and molecular mechanisms revealed that 4-EG suppressed MG activation, mitigated BBB disruption, repressed MMP3/MMP9 production, and inhibited Th1 and Th17 infiltration in the CNS of EAE. Furthermore, 4-EG suppressed Th1 and Th17 differentiation in the periphery of EAE and in vitro Th1 and Th17 cultures. Finally, we found 4-EG induced HO-1 expression in the CNS of EAE in vivo as well as in MG, BV2 cells, and macrophages in vitro.ConclusionsOur work demonstrates that 4-EG confers protection against autoimmune disease EAE through modulating neuroinflammation and inhibiting Th1 and Th17 differentiation, suggesting 4-EG, a natural compound, could be potentially developed as a therapeutic agent for the treatment of MS/EAE.

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Eriocalyxin B ameliorates experimental autoimmune encephalomyelitis by suppressing Th1 and Th17 cells.

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Eriocalyxin B ameliorates experimental autoimmune encephalomyelitis by suppressing Th1 and Th17 cells.

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