Rapamycin Ameliorates Experimental Autoimmune Encephalomyelitis by Suppressing the mTOR-STAT3 Pathway

Abstract

Rapamycin is a new immunosuppressant that has a primarily anti-inflammatory effect and selectively inhibits the activation of T helper (Th)-cell subsets. It is widely used to treat autoimmune disease. We studied the mechanism of rapamycin action against experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, a classic animal model of multiple sclerosis. Rapamycin significantly inhibited the development of EAE by decreasing both clinical scores and inflammatory cell infiltration into the spinal cord. Furthermore, rapamycin reversed EAE symptoms in mice showing the initial signs of paralysis. Rapamycin, is a mammalian target of rapamycin (mTOR) inhibitor. By measuring the downstream markers phospho-mTOR (p-mTOR)/mTOR and phospho-signal transducer and activator of transcription 3 (p-STAT3)/STAT3, we showed that rapamycin suppressed the mTOR-STAT3 pathway in EAE mice. The mTOR-STAT3 signaling pathway is important for Th1 and Th17 cell responses. We found that rapamycin-treated mice had reduced proportions of Th1 and Th17 cells, as well as lower mRNA expression for the transcription factors T-bet and RoRγt in EAE mouse splenocytes. To evaluate Th1 and Th17 cell function, we examined expression of their specific cytokines in the peripheral immune system and central nervous system. Rapamycin treatment reduced protein and mRNA levels of interferon (IFN)-γand interleukin (IL)-17 in splenocytes, and reduced IFN-γ and IL-17 mRNA levels in the spinal cords of EAE mice. These findings suggest that rapamycin treatment inhibits the mTOR-STAT3 pathway in EAE mice, thereby promoting immunosuppression. This study may provide new insight into the mechanism controlling rapamycin effects in multiple sclerosis.

Is interleukin-6 receptor blockade (tocilizumab) beneficial or detrimental to pig-to-baboon organ xenotransplantation?

“…43,44 It can ameliorate inflammation through suppressing the mammalian target of rapamycin-STAT3 pathway in autoimmune encephalomyelitis. 45 In the present study, rapamycin significantly suppressed the human and pig IL-6-activated STAT3 pathways in pAECs and hAECs.…”

“…It is widely used as an immunosuppressant in allotransplant and is also used in xenotransplant . It can ameliorate inflammation through suppressing the mammalian target of rapamycin–STAT3 pathway in autoimmune encephalomyelitis …”

Rapamycin combined with MCC950 to treat multiple sclerosis in experimental autoimmune encephalomyelitis

“…21,22 Its effective expression can help maintain the normal number of related immune cells such as B lymphocytes, CD8 + T cells, and CD4 + T cells. 21,22 Its effective expression can help maintain the normal number of related immune cells such as B lymphocytes, CD8 + T cells, and CD4 + T cells.…”

Therapeutic Potential of Pien Tze Huang on Experimental Autoimmune Encephalomyelitis Rat

“…As reported in previous literatures, STAT3 signaling and NF- κ B signaling are both proinflammatory pathways that can facilitate the expression of cytokines and chemokines [ 36 , 37 ]. The severity of EAE can be alleviated by inhibiting the phosphorylation of STAT3 and/or NF- κ B [ 38 , 39 ]. In addition, PZH was reported to suppress STAT3 signaling and NF- κ B signaling in other diseases [ 15 , 16 ].…”