Natarajan Chandramohan, Muthian Gladson, Barak Yaavov, Evans Ronald M, Bright John J
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
J Immunol. 2003 Dec 1;171(11):5743-50. doi: 10.4049/jimmunol.171.11.5743.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor transcription factor that regulates cell growth, differentiation, and homeostasis. PPARgamma agonists are potent therapeutic agents for type 2 diabetes, obesity, and inflammation. Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of multiple sclerosis. We have shown recently that PPARgamma agonists inhibit EAE by blocking IL-12 production, IL-12 signaling, and neural Ag-induced Th1 differentiation. In this study, we show that the PPARgamma-deficient heterozygous mice develop an exacerbated EAE with prolonged clinical symptoms than the wild-type littermates, following immunization with myelin oligodendrocyte glycoprotein (MOG) p35-55 peptide. The exacerbation of EAE in PPARgamma(+/-) mice associates with an increased expansion of CD4(+) and CD8(+) T cells and expression of CD40 and MHC class II molecules in response to MOGp35-55 Ag. The PPARgamma(+/-) mice also showed an increase in T cell proliferation and Th1 response to MOGp35-55 Ag than the wild-type littermates. These findings suggest that PPARgamma be a critical physiological regulator of CNS inflammation and demyelination in EAE and perhaps multiple sclerosis and other Th1 cell-mediated autoimmune diseases.
过氧化物酶体增殖物激活受体γ（PPARγ）是一种核受体转录因子，可调节细胞生长、分化和体内平衡。PPARγ激动剂是治疗2型糖尿病、肥胖症和炎症的有效药物。实验性自身免疫性脑脊髓炎（EAE）是多发性硬化症的一种Th1细胞介导的炎性脱髓鞘自身免疫疾病模型。我们最近发现，PPARγ激动剂通过阻断IL-12的产生、IL-12信号传导以及神经抗原诱导的Th1分化来抑制EAE。在本研究中，我们发现，在用髓鞘少突胶质细胞糖蛋白（MOG）p35-55肽免疫后，PPARγ缺陷型杂合小鼠比野生型同窝小鼠发生了更严重的EAE，临床症状持续时间更长。PPARγ（+/-）小鼠EAE的加重与CD4（+）和CD8（+）T细胞的扩增增加以及对MOGp35-55抗原反应时CD40和MHC II类分子的表达增加有关。与野生型同窝小鼠相比，PPARγ（+/-）小鼠对MOGp35-55抗原的T细胞增殖和Th1反应也有所增加。这些发现表明，PPARγ是EAE以及可能的多发性硬化症和其他Th1细胞介导的自身免疫疾病中中枢神经系统炎症和脱髓鞘的关键生理调节因子。
