Xu Jihong, Drew Paul D
Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
J Immunol. 2007 Feb 1;178(3):1904-13. doi: 10.4049/jimmunol.178.3.1904.
The IL-12 family of cytokines, which include IL-12, IL-23, and IL-27, play critical roles in the differentiation of Th1 cells and are believed to contribute to the development of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Relatively little is known concerning the expression of IL-12 family cytokines by cells of the CNS, the affected tissue in MS. Previously, we and others demonstrated that peroxisome proliferator-activated receptor (PPAR)-gamma agonists suppress the development of EAE, alter T cell proliferation and phenotype, and suppress the activation of APCs. The present studies demonstrated that PPAR-gamma agonists, including the naturally occurring 15-deoxy-Delta(12,14)-PGJ(2) and the synthetic thiazoladinedione rosiglitazone, inhibited the induction of IL-12p40, IL-12p70 (p35/p40), IL-23 (p19/p40), and IL-27p28 proteins by LPS-stimulated primary microglia. In primary astrocytes, LPS induced the production of IL-12p40, IL-23, and IL-27p28 proteins. However, IL-12p70 production was not detected in these cells. The 15-deoxy-Delta(12,14)-PGJ(2) potently suppressed IL-12p40, IL-23, and IL-27p28 production by primary astrocytes, whereas rosiglitazone suppressed IL-23 and IL-27p28, but not IL-12p40 in these cells. These novel observations suggest that PPAR-gamma agonists modulate the development of EAE, at least in part, by inhibiting the production of IL-12 family cytokines by CNS glia. In addition, we demonstrate that PPAR-gamma agonists inhibit TLR2, MyD88, and CD14 expression in glia, suggesting a possible mechanism by which these agonists modulate IL-12 family cytokine expression. Collectively, these studies suggest that PPAR-gamma agonists may be beneficial in the treatment of MS.
白细胞介素-12细胞因子家族包括白细胞介素-12、白细胞介素-23和白细胞介素-27，在Th1细胞分化中起关键作用，并且被认为与多发性硬化症（MS）及实验性自身免疫性脑脊髓炎（EAE，一种MS的动物模型）的发病有关。关于中枢神经系统（CNS，MS中的病变组织）细胞中白细胞介素-12细胞因子家族的表达情况，人们了解相对较少。此前，我们和其他人证明过，过氧化物酶体增殖物激活受体（PPAR）-γ激动剂可抑制EAE的发病，改变T细胞增殖和表型，并抑制抗原呈递细胞（APC）的激活。目前的研究表明，PPAR-γ激动剂，包括天然存在的15-脱氧-Δ（12,14）-前列腺素J2（15-deoxy-Delta(12,14)-PGJ(2)）和合成噻唑烷二酮类药物罗格列酮，可抑制脂多糖（LPS）刺激的原代小胶质细胞诱导白细胞介素-12p40、白细胞介素-12p70（p35/p40）、白细胞介素-23（p19/p40）和白细胞介素-27p28蛋白的产生。在原代星形胶质细胞中，LPS可诱导白细胞介素-12p40、白细胞介素-23和白细胞介素-27p28蛋白的产生。然而，在这些细胞中未检测到白细胞介素-12p70的产生。15-脱氧-Δ（12,14）-前列腺素J2可有效抑制原代星形胶质细胞产生白细胞介素-12p40、白细胞介素-23和白细胞介素-27p28，而罗格列酮可抑制这些细胞中白细胞介素-23和白细胞介素-27p28的产生，但不能抑制白细胞介素-12p40的产生。这些新发现表明，PPAR-γ激动剂至少部分地通过抑制CNS神经胶质细胞产生白细胞介素-12细胞因子家族来调节EAE的发病。此外，我们证明PPAR-γ激动剂可抑制神经胶质细胞中Toll样受体2（TLR2）、髓样分化因子88（MyD88）和CD14的表达，提示这些激动剂调节白细胞介素-12细胞因子家族表达的一种可能机制。总体而言，这些研究表明PPAR-γ激动剂可能对MS的治疗有益。
