Progranulin inhibits expression and release of chemokines CXCL9 and CXCL10 in a TNFR1 dependent manner.
Progranulin inhibits expression and release of chemokines CXCL9 and CXCL10 in a TNFR1 dependent manner.
复制标题
DOI：
10.1038/srep21115
复制
发表时间：
2016-02-19
影响因子：
4.6
通讯作者：
Liu CJ
中科院分区：
文献类型：
--
作者：
Mundra JJ;Jian J;Bhagat P;Liu CJ
颗粒蛋白前体（PGRN）是一种多营养生长因子，在维持和调节正常组织发育、增殖、再生和宿主防御的动态平衡中发挥重要作用。PGRN还具有有效的抗炎功能，并且失调的PGRN与类风湿性关节炎和炎性肠病相关。我们以前报道过PGRN直接与TNFR结合并显著增强Treg群体和刺激IL-10的产生。为了进一步研究PGRN在免疫系统中的功能，我们对来自野生型B6小鼠和PGRN −/−小鼠的CD 4 + T细胞进行了基因阵列分析。我们鉴定了许多趋化因子及其受体，其中CXCL 9和CXCL 10是最突出的，其在PGRN敲除小鼠中被显著诱导。给予重组PGRN蛋白强烈抑制TNF和IFN-γ诱导的CXCL 9和CXCL 10表达。此外，CXCL 9表达在PGRN KO小鼠中强烈上调，并且其水平与皮炎模型中的炎症严重程度相关。此外，我们已经证明PGRN介导的趋化因子表达的抑制在很大程度上取决于TNFR 1。总而言之，这项研究为PGRN介导的各种炎症和自身免疫性疾病调节的机制提供了新的见解。
Progranulin (PGRN), a pleiotrophic growth factor, is known to play an important role in the maintenance and regulation of the homeostatic dynamics of normal tissue development, proliferation, regeneration, and host-defense. PGRN also has potent anti-inflammatory functionality, and deregulated PGRN is associated with rheumatoid arthritis and inflammatory bowel disease. We have previously reported that PGRN directly binds to TNFR and significantly enhances Treg population and stimulatesIL-10 production. To further investigate PGRN’s function in the immune system we performed a gene array analysis on CD4+ T cells from wild type B6 mice and PGRN −/− mice. We identified many chemokines and their receptors, among which CXCL9 and CXCL10 were most prominent, that were significantly induced in PGRN null mice. Administration of recombinant PGRN protein strongly inhibited TNF and IFN-γ-induced CXCL9 and CXCL10 expression. In addition, CXCL9 expression is strongly upregulated in PGRN KO mice and its level is correlated with severity of inflammation in a dermatitis model. Further, we have demonstrated that PGRN-mediated inhibition of chemokine expression largely depends on TNFR1. Taken together, this study provides new insights into the mechanisms underlying PGRN mediated regulation of various inflammatory and autoimmune diseases.