Amelioration of Experimental Autoimmune Encephalomyelitis by Plumbagin through Down-Regulation of JAK-STAT and NF-κB Signaling Pathways

Abstract

Plumbagin(PL), a herbal compound derived from roots of the medicinal plant Plumbago zeylanica, has been shown to have immunosuppressive properties. Present report describes that PL is a potent novel agent in control of encephalitogenic T cell responses and amelioration of mouse experimental autoimmune encephalomyelitis (EAE), through down-regulation of JAK-STAT pathway. PL was found to selectively inhibit IFN-γ and IL-17 production by CD4+ T cells, which was mediated through abrogated phosphorylation of JAK1 and JAK2. Consistent with IFN-γ and IL-17 reduction was suppressed STAT1/STAT4/T-bet pathway which is critical for Th1 differentiation, as well as STAT3/ROR pathway which is essential for Th17 differentiation. In addition, PL suppressed pro-inflammatory molecules such as iNOS, IFN-γ and IL-6, accompanied by inhibition of IκB degradation as well as NF-κB phosphorylation. These data give new insight into the novel immune regulatory mechanism of PL and highlight the great value of this kind of herb compounds in probing the complex cytokine signaling network and novel therapeutic targets for autoimmune diseases.

Therapeutic Efficacy of Suppressing the JAK/STAT Pathway in Multiple Models of Experimental Autoimmune Encephalomyelitis

“…The protective effect of GA in EAE is in part due to inhibition of STAT4 and STAT3 phosphorylation in T-cells, altering Th1 and Th17 cell differentiation, respectively (67). Two herbal compounds, plumbagin (PL) and berberine, exert protective effects in EAE models by inhibiting STAT activation and Th1 and Th17 cell differentiation (68, 69). In this study, we have utilized a specific inhibitor of the JAK/STAT pathway, AZD1480, and documented a striking beneficial immunomodulatory effect in five different models of EAE.…”

Opportunities for Translation from the Bench: Therapeutic Intervention of the JAK/STAT Pathway in Neuroinflammatory Diseases

“…Interestingly, BM treatment up-regulated expression of STAT-interacting LIM protein (SLIM), an ubiquitin E3 ligase for STAT4, which promotes STAT4 degradation, resulting in markedly decreased IFN-γ production in CD4 + T cells from EAE mice. 142 The same group showed that another natural compound, Berberine (BBR), an isoquinoline alkaloid derived from plants, is able to influence Th1 and Th17 cell differentiation and ameliorate EAE disease by targeting activation of TYK2/ JAK1/2/STAT1/4 in Th1 cells and STAT3 in Th17 cells. 143 Studies from the Bright group have shown that three natural compounds, curcumin (a naturally occurring polyphenolic phytochemical isolated from rhizomes of the medicinal plant Curcuma longa ), 144 quercetin (a flavonoid phytoestrogen), 145 and 1,25 dihydroxyvitamin-D3 146 can individually inhibit EAE development by suppressing IL-12–induced JAK2/ TYK2/STAT3/4 activation.…”

Involvement of JAK/STAT signaling in the effect of cornel iridoid glycoside on experimental autoimmune encephalomyelitis amelioration in rats

“…AZD1480, a specific inhibitor of the JAK/STAT pathway, showed a striking beneficial immunomodulatory effect in five different models of EAE (Liu et al, 2014). Two herbal compounds, plumbagin and berberine, exert protective effects in EAE models by inhibiting STAT activation and Th1 and Th17 cell differentiation (Qin et al, 2010;Jia et al, 2011). The precise protective mechanism of CIG on neuroinflammatory responses still needs to be elucidated.…”