Chemical probing reveals insights into the signaling mechanism of inflammasome activation
Chemical probing reveals insights into the signaling mechanism of inflammasome activation
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DOI：
10.1038/cr.2010.135
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发表时间：
2010-12-01
期刊：
影响因子：
44.1
通讯作者：
Shao, Feng
中科院分区：
文献类型：
--
作者：
Gong, Yi-Nan;Wang, Xiaoming;Shao, Feng
Caspase-1介导的IL-1β的产生一般受两条途径控制。Toll样受体(TLRs)识别病原体衍生的产物并诱导依赖于NF-kappa B的前IL-1β转录；Nod样受体(NLRs)组装激活caspase-1的炎症体复合体，感知细菌产物/危险信号。通过有针对性的化学筛选，我们确定了海洋天然产物溴氧酮是caspase-1途径的特异和有效的抑制物。溴莫酮对多种炎症刺激有效，包括TLR配体加ATP/黑素、胞浆DNA、鞭毛蛋白和炭疽杆菌致命毒素。溴氧酮还有效地抑制由几种类型的细菌感染引发的caspase-1激活。溴氧酮以一种不依赖转录的方式在炎症体的上游或水平上起作用。溴氧酮还通过靶向TLR-NF-kappa B途径中IKK上游的成分来抑制前IL-1β的表达。溴氧酮独特的双重活性被已知的TAK1抑制剂所共享，该抑制剂专门阻断NALP3炎症体的激活。根据溴氧酮的机制和药理学特性，我们进一步发现，几种已知的作用于IKK上游但不针对IKK或IKK下游的核因子-kappaB抑制剂，是NLRs介导的不同caspase-1激活的有效阻断剂。我们的研究揭示了NLR(NALP3)介导的炎症体途径和TLR-NF-kappa B信号之间可能存在的非转录分子联系，并提出了开发新的抗炎药物的潜在策略。
Caspase-1-mediated IL-1 beta production is generally controlled by two pathways. Toll-like receptors (TLRs) recognize pathogen-derived products and induce NF-kappa B-dependent pro-IL-1 beta transcription; NOD-like receptors (NLRs) assemble caspase-1-activating inflammasome complexes that sense bacterial products/danger signals. Through a targeted chemical screen, we identify bromoxone, a marine natural product, as a specific and potent inhibitor of the caspase-1 pathway. Bromoxone is effective over diverse inflammatory stimuli including TLR ligands plus ATP/nigericin, cytosolic DNA, flagellin and Bacillus anthracis lethal toxin. Bromoxone also efficiently suppresses caspase-1 activation triggered by several types of bacterial infection. Bromoxone acts upstream or at the level of the inflammasome in a transcription-independent manner. Bromoxone also inhibits pro-IL-1 beta expression by targeting components upstream of IKK in the TLR-NF-kappa B pathway. The unique dual activities of bromoxone are shared by the known TAK1 inhibitor that specifically blocks Nalp3 inflammasome activation. Hinted from the mechanistic and pharmacological properties of bromoxone, we further discover that several known NF-kappa B inhibitors that act upstream of IKK, but not those targeting IKK or IKK downstream, are potent blockers of different NLRs-mediated caspase-1 activation. Our study uncovers a possible non-transcriptional molecular link between the NLR (Nalp3)-mediated inflammasome pathway and TLR-NF-kappa B signaling, and suggests a potential strategy to develop new anti-inflammatory drugs.