Aberrant toll receptor expression and endotoxin hypersensitivity in mice lacking a functional TGF-β1 signaling pathway
Aberrant toll receptor expression and endotoxin hypersensitivity in mice lacking a functional TGF-β1 signaling pathway
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DOI：
10.4049/jimmunol.172.6.3814
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发表时间：
2004-03-15
影响因子：
4.4
通讯作者：
Wahl, SM
中科院分区：
文献类型：
--
作者：
McCartney-Francis, N;Jin, WW;Wahl, SM
TGF-β1 在维持正常免疫功能中发挥着核心作用，这种有效的免疫抑制分子的缺乏与不受控制的炎症、恶病质和多器官衰竭有关，如在 TGF-β1 缺失小鼠中所见。炎症细胞浸润到裸鼠的重要器官中，伴随着炎症细胞因子基因表达的增加，包括 TNF-α 和 IL-1β，以及诱导型 NO 合酶，每种细胞因子均受 NF-κB 调节。用蛋白酶体抑制剂 MG132 治疗以防止 NF-κB 激活，可显着减少 NO 的产生和炎症细胞因子的表达。在没有任何可识别病原体的情况下，TGF-β1 缺失小鼠中 NF-κB 激活的炎症表型表明先天免疫反应的激活。由于 Toll 样受体 (TLR) 在先天免疫的激活中至关重要，因此我们检测了 TGF-β1 缺失小鼠和野生型小鼠的炎症组织中 TLR4 的表达情况，TLR4 是一种与细菌细胞壁 LPS 相互作用的受体，启动 NF-κB 依赖性信号通路，从而导致炎症介质的基因转录。在 TGF-β1 缺失小鼠以及缺乏 TGF-β 转录因子 Smad3 的小鼠中观察到 TLR4 mRNA 表达增加，与 LPS 高反应性相关，导致炎性细胞因子和 NO 表达增加以及内毒素血症。此外，同时缺乏 TGF-β1 和功能性 TLR4 的小鼠能够抵抗内毒素休克。在没有 TGF-β 抑制的情况下，TLR4 和下游元件的组成性和/或环境激活可能会影响先天性和适应性免疫，并导致大规模不受控制的炎症。
TGF-beta1 plays a central role in maintaining normal immune function and deficiency of this potent immunosuppressive molecule is linked to uncontrolled inflammation, cachexia, and multiorgan failure as seen in the TGF-beta1 null mouse. Infiltration of inflammatory cells into vital organs of the null mouse is accompanied by increased gene expression of inflammatory cytokines, including TNF-alpha and IL-1beta, as well as inducible NO synthase, each regulated by NF-kappaB. Treatment with the proteasome inhibitor MG132 to prevent NF-kappaB activation dramatically reduced NO production and expression of inflammatory cytokines. This inflammatory phenotype with NF-kappaB activation in the TGF-beta1 null mouse, in the absence of any identifiable pathogen, suggested activation of innate immune responses. Because Toll-like receptors (TLR) are essential in the activation of innate immunity, we examined inflamed tissue from TGF-beta1 null and wild-type mice for expression of TLR4, the receptor that interacts with bacterial cell wall LPS to initiate an NF-kappaB-dependent signaling pathway, leading to gene transcription of inflammatory mediators. Increased TLR4 mRNA expression observed in TGF-beta1 null mice as well as in mice lacking the TGF-beta transcription factor Smad3 was associated with LPS hyperresponsiveness leading to increased expression of inflammatory cytokines and NO and endotoxemia. Furthermore, mice lacking both TGF-beta1 and a functional TLR4 were resistant to endotoxin shock. Constitutive and/or environmental activation of TLR4 and downstream elements, in the absence of TGF-beta suppression, may impact on innate and adaptive immunity and contribute to massive uncontrolled inflammation.