5-Aminoimidazole-4-carboxamide ribonucleoside: A novel immunomodulator with therapeutic efficacy in experimental autoimmune encephalomyelitis
5-Aminoimidazole-4-carboxamide ribonucleoside: A novel immunomodulator with therapeutic efficacy in experimental autoimmune encephalomyelitis
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DOI：
10.4049/jimmunol.175.1.566
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发表时间：
2005-07-01
影响因子：
4.4
通讯作者：
Singh, I
中科院分区：
文献类型：
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作者：
Nath, N;Giri, S;Singh, I
实验性自身免疫性脑脊髓炎（EAE）是一种多发性硬化的动物模型，是一种Th 1介导的中枢神经系统炎性脱髓鞘疾病。最近有报道称，AMP活化的蛋白激酶通过负调节NF-κ B信号传导而具有抗炎活性。在这项研究中，我们研究了AMP激活的蛋白激酶激活剂5-氨基咪唑-4-甲酰胺核糖核苷（AICAR）在PLP 139 -151或MOG（35-55）主动免疫诱导的主动和被动EAE中的预防和治疗效果，以及PLP 139 -151致敏的T细胞过继转移。AICAR的体内治疗对EAE具有预防和治疗作用，减轻了临床疾病的严重程度。AICAR的抗炎作用与抑制Ag特异性回忆反应和抑制Th 1型细胞因子IFN-γ和TNF-α有关，而它诱导产生Th 2型细胞因子IL-4和IL-10。在体外用AICAR处理PLP 139 -151特异性T细胞降低了它们响应于IL-12（Th 1转录因子）的T-bet的表达，而响应于IL-4，AICAR分别诱导Th 2转录因子GATA 3和STAT 6的表达和磷酸化。此外，在体外用AICAR处理APC抑制了它们将蛋白脂质蛋白肽呈递给PLP 139 -151特异性T细胞的能力。在一个无关的Th 1介导的OT-2 TCR转基因小鼠模型中，AICAR损害了体内CD 4（+）T细胞的Ag特异性扩增。总之，这些发现首次表明AICAR是一种新型免疫调节剂，对治疗多发性硬化症和其他Th 1介导的炎症性疾病具有良好的有益作用。
Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, is a Th1-mediated inflammatory demyelinating disease of the CNS. AMP-activated protein kinase was reported recently to have anti-inflammatory activities by negatively regulating NF-kappa B signaling. In this study, we investigated the prophylactic and therapeutic efficacy of an AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), in active and passive EAE induced by active immunization with PLP139-151 or MOG(35-55) and in adoptive transfer of PLP139-151-sensitized T cells, respectively. In vivo treatment with AICAR exerted both prophylactic and therapeutic effects on EAE, attenuating the severity of clinical disease. The anti-inflammatory effects of AICAR were associated with the inhibition of the Ag-specific recall responses and inhibition of the Th1-type cytokines IFN-gamma and TNF-alpha, whereas it induced the production of Th2 cytokines IL-4 and IL-10. Treatment of PLP139-151-specific T cells in vitro with AICAR decreased their expression of T-bet in response to IL-12, a Th1 transcription factor, whereas in response to IL-4, it induced the expression and phosphorylation of Th2 transcription factors GATA3 and STAT6, respectively. Moreover, treatment of APCs in vitro with AICAR inhibited their capability to present the proteolipid protein peptide to PLP139-151-specific T cells. In an irrelevant Th1-mediated, OT-2 TCR transgenic mouse model, AICAR impaired in vivo Ag-specific expansion of CD4(+) T cells. Together, these findings show for the first time that AICAR is a novel immunomodulator with promising beneficial effects for the treatment of multiple sclerosis and other Th1-mediated inflammatory diseases.