Glucocorticoid-induced tumor necrosis factor receptor-related (GITR)-Fc fusion protein inhibits GITR triggering and protects from the inflammatory response after spinal cord injury
Glucocorticoid-induced tumor necrosis factor receptor-related (GITR)-Fc fusion protein inhibits GITR triggering and protects from the inflammatory response after spinal cord injury
复制标题
DOI：
10.1124/mol.107.044354
复制
发表时间：
2008-06-01
影响因子：
3.6
通讯作者：
Riccardi, Carlo
中科院分区：
文献类型：
--
作者：
Nocentini, Giuseppe;Cuzzocrea, Salvatore;Riccardi, Carlo
糖皮质激素诱导的肿瘤坏死因子受体相关蛋白(GITR)是一种协同刺激分子，在炎症中发挥作用，使GITR-Fc融合蛋白发挥抗炎作用。为了探讨GITR-Fc发挥作用的机制，我们首先使用GITR基因敲除(GITR(-/-))小鼠来验证GITR配体(GITRL)/GITR系统在脊髓损伤(SCI)模型中是否发挥促炎作用。值得注意的是，与GITR(-/-)小鼠相比，GITR(-/-)小鼠诱发的疾病不那么明显。然后，我们评估了GITR-Fc融合蛋白对GITR(-/-)和野生型(GITR(-/-))小鼠脊髓损伤的保护作用。GITR-Fc可通过以下方面减轻GITR(-/-)小鼠脊髓损伤后的炎症反应：1)组织学损伤和细胞凋亡，2)凋亡相关转导因子(Bax和Bcl2)的调节，3)炎症标志物[硝基酪氨酸、诱导型一氧化氮合酶、白介素2、IL-12和肿瘤坏死因子-α]的表达，以及4)T淋巴细胞的浸润。GITR-FC对GITR(-/-)有效，但对GITR(-/-)无效，提示在本实验模型中，其抗炎作用是通过抑制GITR的触发而不是通过激活GITRL实现的。综上所述，GITR在脊髓损伤中起一定作用，GITR-FC的应用可改善SCI的严重程度，促进对GITR-FC潜在抗炎特性的进一步研究。
Glucocorticoid-induced tumor necrosis factor receptor-related (GITR) protein is a costimulatory molecule that plays a role in inflammation so that GITR-Fc fusion protein can exert an anti-inflammatory effect. To investigate the mechanism by which GITR-Fc exerts its effects, we first used GITR knock-out (GITR(-/-)) mice to verify whether GITR ligand (GITRL)/GITR system played a pro-inflammatory role in the spinal cord injury (SCI) model. It is noteworthy that less pronounced disease was induced in GITR(-/-) compared with GITR(-/-) mice. We then evaluated the effect of GITR-Fc fusion protein against SCI-induced injuries in GITR(-/-) and wild-type (GITR(-/-)) mice. Administration of GITR-Fc ameliorated SCI-induced inflammation in GITR(-/-) mice as evaluated through: 1) histological damage and apoptosis, 2) modulation of apoptosis-related transduction factors (Bax and Bcl-2), 3) expression of inflammatory markers [nitrotyrosine, inducible nitric-oxide synthase, interleukin (IL)-2, IL-12, and tumor necrosis factor-alpha], and 4) T-lymphocyte infiltration. GITR-Fc was effective in GITR(-/-) but not in GITR(-/-), suggesting that in this experimental model, its anti-inflammatory action was due to inhibition of GITR triggering and not to GITRL activation. In conclusion, GITR plays a role in SCI, and administration of GITR-Fc results in amelioration of SCI severity, prompting further studies on the potential anti-inflammatory properties of GITR-Fc.