Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis
Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis
复制标题
DOI：
10.1172/jci26523
复制
发表时间：
2006-02-01
影响因子：
15.9
通讯作者：
Matarese, G
中科院分区：
文献类型：
--
作者：
De Rosa, V;Procaccini, C;Matarese, G
最近的证据表明，瘦素是一种脂肪细胞分泌的激素，属于螺旋细胞因子家族，显著影响免疫和自身免疫反应。在此，我们研究了在体内消除瘦素作用保护SJL/J小鼠免受蛋白脂蛋白肽plp139 -151诱导的EAE的机制，这是一种ms动物模型。在EAE发生之前或之后，用瘦素和瘦素抗体或可溶性小鼠瘦素受体嵌合体（ObR:Fc）阻断瘦素，可以改善临床评分，减缓疾病进展，减少疾病复发，抑制plp139 -151特异性T细胞增殖。并将细胞因子分泌转向Th2/调控谱。在瘦素中和小鼠的CD4(+) T细胞中诱导叉头盒p3 （Foxp3）表达也证实了这一点。重要的是，抗瘦素治疗导致自身反应性CD4(+) T细胞中细胞周期蛋白依赖性激酶抑制剂p27（p27(Kip-1)）下调失败。这些作用与ERK1/2和STAT6酪氨酸磷酸化增加有关。综上所述，我们的数据为EAE中瘦素拮抗提供了新的分子基础，并展望了基于瘦素的分子靶向治疗该病的新策略。
Recent evidence has indicated that leptin, an adipocyte-secreted hormone belonging to the helical cytokine family, significantly influences immune and autoimmune responses. We investigate here the mechanisms by which in vivo abrogation of leptin effects protects SJL/J mice from proteolipid protein peptide PLP139-151-induced EAE, an animal model of MS. Blockade of leptin with and-leptin Abs or with a soluble mouse leptin receptor chimera (ObR:Fc), either before or after onset of EAE, improved clinical score, slowed disease progression, reduced disease relapses, inhibited PLP139-151-specific T cell proliferation, and switched cytokine secretion toward a Th2/regulatory profile. This was also confirmed by induction of forkhead box p3 (Foxp3) expression in CD4(+) T cells in leptin-neutralized mice. Importantly, anti-leptin treatment induced a failure to downmodulate the cyclin-dependent kinase inhibitor p27 (p27(Kip-1)) in autoreactive CD4(+) T cells. These effects were associated with increased tyrosine phosphorylation of both ERK1/2 and STAT6. Taken together, our data provide what we believe is a new molecular basis for leptin antagonism in EAE and envision novel strategies of leptin-based molecular targeting in the disease.