Division of Nephrology, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan.
J Investig Med. 2011 Oct;59(7):1141-6. doi: 10.2310/JIM.0b013e31822ba7fb.
Angiotensin-converting enzyme inhibitors (ACEIs) are used to control hypertension and are superior to other antihypertensive agents in protecting the progressive deterioration of autoimmune-related nephritis. An imbalance of T helper 1 (Th1)/Th2 is thought to contribute to the pathogenesis of autoimmune diseases and their related glomerulonephritis. I-309 is a Th2-related chemokine involved in the recruitment of Th2 cells toward Th2-related inflammation. Tumor necrosis factor α (TNF-α) and Th1-related chemokines, interferon-inducible protein 10 (IP-10)/CXCL10 are also involved in autoimmune glomerulonephritis. However, the modulatory effects and the mechanisms of ACEIs on TNF-α and Th1- and Th2-related chemokines in monocytes remain poorly defined.
We investigated the effects of imidapril and perindopril, 2 ACEIs, on the expression of IP-10, I-309, and TNF-α in human monocytes and also the associated intracellular mechanism.
Imidapril and perindopril significantly downregulated lipopolysaccharide (LPS)-induced TNF-α, I-309, and IP-10 in THP-1 cells and human primary monocytes. All 3 mitogen-activated protein kinase inhibitors suppressed LPS-induced TNF-α and I-309 expression in human primary monocytes. Only extracellular signal-regulated kinases and c-Jun N-terminal kinases (JNK) mitogen-activated protein kinase inhibitors suppressed LPS-induced IP-10 expression. Lipopolysaccharide-induced mitogen-activated protein kinase kinase 4 (MKK4), p-JNK, and c-Jun expression in human primary monocytes was suppressed by imidapril.
These data demonstrate that ACEI is effective in downregulating LPS-induced TNF-α, I-309, and IP-10, which play important roles in the pathogenesis of inflammation. Its suppressive effect on TNF-α, I-309, and IP-10 may, at least in part, involve the down-regulation of LPS-induced MKK4-JNK-c-Jun expression.
血管紧张素转换酶抑制剂（ACEI）用于控制高血压，在保护自身免疫性相关肾炎的进行性恶化方面优于其他降压药物。辅助性 T 细胞 1（Th1）/Th2 失衡被认为有助于自身免疫性疾病及其相关肾小球肾炎的发病机制。I-309 是一种与 Th2 相关的趋化因子，参与了 Th2 细胞向 Th2 相关炎症的募集。肿瘤坏死因子 α（TNF-α）和 Th1 相关趋化因子干扰素诱导蛋白 10（IP-10）/CXCL10 也参与自身免疫性肾小球肾炎。然而，ACEI 对单核细胞中 TNF-α 和 Th1-和 Th2 相关趋化因子的调节作用及其机制仍不清楚。
我们研究了 2 种 ACEI，依那普利和培哚普利，对人单核细胞中 IP-10、I-309 和 TNF-α表达的影响，以及相关的细胞内机制。
依那普利和培哚普利显著下调了脂多糖（LPS）诱导的 THP-1 细胞和人原代单核细胞中 TNF-α、I-309 和 IP-10 的表达。所有 3 种丝裂原活化蛋白激酶抑制剂均抑制了 LPS 诱导的人原代单核细胞中 TNF-α和 I-309 的表达。只有细胞外信号调节激酶和 c-Jun N-末端激酶（JNK）丝裂原活化蛋白激酶抑制剂抑制了 LPS 诱导的 IP-10 表达。LPS 诱导的人原代单核细胞中丝裂原活化蛋白激酶激酶 4（MKK4）、p-JNK 和 c-Jun 的表达被依那普利抑制。
这些数据表明，ACEI 能有效下调 LPS 诱导的 TNF-α、I-309 和 IP-10 的表达，这些因子在炎症发病机制中起着重要作用。其对 TNF-α、I-309 和 IP-10 的抑制作用至少部分涉及 LPS 诱导的 MKK4-JNK-c-Jun 表达的下调。
