Asai Germanium Research Institute Co., Ltd. Suzuranoka 3-131, Hakodate 042-0958, Hokkaido, Japan.
Laboratory of Animal Health Science, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Miyagi, Japan.
Int J Mol Sci. 2022 Nov 1;23(21):13364. doi: 10.3390/ijms232113364.
Inflammasome activity is a key indicator of inflammation. The inflammasome is activated by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), which activate the p38-NF-κB pathway and promote IL-1β transcription (signaling step 1). Next, extracellular adenosine triphosphate (ATP) activates the inflammasome (a protein complex consisting of a signal recognition protein, an adapter protein, and Caspase-1) and secretion of inflammatory cytokines such as IL-1β (signaling step 2). Inflammasome activation causes excessive inflammation, leading to inflammasome-active diseases such as atherosclerosis and type 2 diabetes. A hydrolysate of the organogermanium compound Ge-132, 3-(Trihydroxygermyl) propanoic acid (THGP) can form a complex with a cis-diol structure. We investigated the inhibitory effect of THGP on inflammasome activity in human THP-1 monocytes. THGP inhibited IL-1β secretion and caspase-1 activation (signaling step 2) in an ATP-dependent manner. On the other hand, THGP did not suppress IL-1β secretion induced by only lipopolysaccharide (LPS) stimulation. In addition, as IL-6 is an ATP-independent inflammatory cytokine, THGP did not decrease its secretion. THGP also suppressed pyroptosis, which is a caspase-1 activity-dependent form of cell death. Therefore, THGP is expected to become a new therapeutic or prophylactic agent for inflammasome-associated diseases.
炎症小体活性是炎症的一个关键指标。炎症小体被病原体相关分子模式 (PAMPs) 和损伤相关分子模式 (DAMPs) 激活，激活 p38-NF-κB 途径并促进 IL-1β 转录（信号步骤 1）。接下来，细胞外三磷酸腺苷 (ATP) 激活炎症小体（一种由信号识别蛋白、衔接蛋白和 Caspase-1 组成的蛋白复合物）并分泌白细胞介素-1β等炎症细胞因子（信号步骤 2）。炎症小体的激活会导致过度炎症，从而引发动脉粥样硬化和 2 型糖尿病等炎症小体活性疾病。有机锗化合物 Ge-132 的水解产物 3-(三羟基锗基)丙酸 (THGP) 可以与顺二醇结构形成复合物。我们研究了 THGP 对人 THP-1 单核细胞中炎症小体活性的抑制作用。THGP 以 ATP 依赖性方式抑制 IL-1β 的分泌和 Caspase-1 的激活（信号步骤 2）。另一方面，THGP 不能抑制仅由脂多糖 (LPS) 刺激诱导的 IL-1β 分泌。此外，由于白细胞介素-6 是一种非依赖于 ATP 的炎症细胞因子，THGP 不会减少其分泌。THGP 还抑制了细胞焦亡，这是一种依赖于 Caspase-1 活性的细胞死亡形式。因此，THGP 有望成为炎症小体相关疾病的新型治疗或预防药物。
