Cutting edge: Tissue inhibitor of metalloproteinase 3 regulates TNF-dependent systemic inflammation
Cutting edge: Tissue inhibitor of metalloproteinase 3 regulates TNF-dependent systemic inflammation
复制标题
DOI：
10.4049/jimmunol.176.2.721
复制
发表时间：
2006-01-15
影响因子：
4.4
通讯作者：
Khokha, R
中科院分区：
文献类型：
--
作者：
Smookler, DS;Mohammed, FF;Khokha, R
宿主对感染性病原体的反应必须迅速而有力。一种机制是释放预先合成的膜结合的肿瘤坏死因子。肿瘤坏死因子的释放由肿瘤坏死因子-α转换酶介导，金属蛋白酶组织抑制因子3(TIMP3)选择性地抑制肿瘤坏死因子的释放。我们发现，TIMP3的缺失通过失调肿瘤坏死因子及其受体的裂解而影响先天免疫。培养的TIMP3(-/-)巨噬细胞比野生型巨噬细胞释放更多的肿瘤坏死因子。在TIMP3(-/-)小鼠中，与野生型小鼠相比，内毒素导致血清中肿瘤坏死因子及其受体水平上升得更快，并保持在较高水平。TIMP3(-/-)小鼠血清IL-6水平升高表明，TIMP3(-/-)小鼠体内配体和受体脱落的动力学改变增强了肿瘤坏死因子信号转导，从生理意义上讲，TIMP3(-/-)小鼠对脂多糖诱导的死亡更敏感。去除肿瘤坏死因子受体基因p55(Tnfrsf1a)或用合成的金属蛋白酶抑制剂治疗可以拯救TIMP3(-/-)小鼠。因此，TIMP3对于正常的先天性免疫功能是必不可少的。
Host response to infectious agents must be rapid and powerful. One mechanism is the release of presynthesized membrane-bound TNF. TNF shedding is mediated by TNF-alpha converting enzyme, which is selectively inhibited by the tissue inhibitor of metalloproteinase 3 (TIMP3). We, show that loss of TIMP3 impacts innate immunity by dysregulating cleavage of TNF and its receptors. Cultured timp3(-/-) macrophages release more TNF in response to LPS than wild-type macrophages. In timp3(-/-) mice, LPS causes serum levels of TNF and its receptors to rise more rapidly and remain higher compared with wild-type mice. The altered kinetics of ligand and receptor shedding enhances TNF signaling in timp3(-/-) mice, indicated by elevated serum IL-6 Physiologically, timp3(-/-) mice are more susceptible to LPS-induced mortality. Ablation of the TNF receptor gene p55 (Tnfrsf1a) or treatment with a synthetic metalloproteinase inhibitor rescues timp3(-/-) mice. Thus, TIMP3 is essential for normal innate immune function.