Acquisition of Anergy to Proinflammatory Cytokines in Nonimmune Cells through Endoplasmic Reticulum Stress Response: A Mechanism for Subsidence of Inflammation
Acquisition of Anergy to Proinflammatory Cytokines in Nonimmune Cells through Endoplasmic Reticulum Stress Response: A Mechanism for Subsidence of Inflammation
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DOI：
10.4049/jimmunol.182.2.1182
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发表时间：
2009-01-15
影响因子：
4.4
通讯作者：
Kitamura, Masanori
中科院分区：
文献类型：
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作者：
Hayakawa, Kunihiro;Hiramatsu, Nobuhiko;Kitamura, Masanori
急性内质网（ER）应激通过激活NF-κ B引起炎症分子的诱导。然而，我们发现，在内质网应激条件下，肾系膜细胞获得无反应性促炎刺激。用ER应激诱导剂（衣霉素、毒胡萝卜素、A23187和AB，枯草杆菌酶细胞毒素）引发细胞引起MCP-1响应于TNF-α、IL-1 β、巨噬细胞衍生因子或旁观者巨噬细胞的钝化诱导。抑制的幅度与内质网应激的内源性指标GRP78的水平密切相关。MCP-1在ER应激条件下的抑制是可逆的，并且通常观察到与细胞类型或ER应激的触发因素无关。MCP-1 mRNA水平的降低归因于通过意外抑制NF-κ B的转录抑制，而不是加速mRNA降解。随后的实验表明，TNFR相关因子2，TNF-α信号转导的重要组成部分，下调ER应激。我们还发现，在ER应激条件下，NF-κ B B抑制因子A20的表达被诱导。A20的过表达导致对奎宁触发的NF-κ B活化的抑制，并且通过RNA干扰敲低A20显著减弱了ER应激诱导的无反应性。相反，其它可抑制NF-κ B的ER应激诱导/相关分子（例如，GRP78、NO、活性氧和I κ B）不参与内质网应激的抑制作用。这些结果阐明了ER应激依赖的机制，通过该机制，非免疫细胞在病理情况下获得对炎症刺激的无反应性。这种自我防御机制可能在阻止急性炎症的进展及其自发消退中发挥作用。免疫学杂志，2009，182：1182 - 1191.
Acute endoplasmic reticulum (ER) stress causes induction of inflammatory molecules via activation of NF-kappa B. However, we found that, under ER stress conditions, renal mesangial cells acquire anergy to proinflammatory stimuli. Priming of the cells with ER stress inducers (tunicamycin, thapsigargin, A23187, and AB, subtilase cytotoxin) caused blunted induction of MCP-1 in response to TNF-alpha, IL-1 beta, macrophage-derived factors, or bystander macrophages. The magnitude of suppression was closely correlated with the level of GRP78, an endogenous indicator of ER stress. The suppression of MCP-1 under ER stress conditions was reversible and observed in general regardless of cell types or triggers of ER stress. The decrease in the level of MCP-1 mRNA was ascribed to transcriptional suppression via unexpected inhibition of NF-kappa B, but not to accelerated mRNA degradation. Subsequent experiments revealed that TNFR-associated factor 2, an essential component for TNF-a signaling, was down-regulated by ER stress. We also found that, under ER stress conditions, expression of NF-kappa B suppressor A20 was induced. Overexpression of A20 resulted in suppression of cytokine-triggered NF-kappa B activation and knockdown of A20 by RNA interference significantly attenuated induction of anergy by ER stress. in contrast, other ER stress-inducible/-related molecules that may suppress NF-kappa B (e.g., GRP78, NO, reactive oxygen species, and I kappa B) were not involved in the inhibitory effects of ER stress. These results elucidated ER stress-dependent mechanisms by which nonimmune cells acquire anergy to inflammatory stimuli under pathological situations. This self-defense machinery may play a role in halting progression of acute inflammation and in its spontaneous subsidence. The Journal of Immunology, 2009, 182: 1182-1191.