Kinin B1 and B2 receptor expression in osteoblasts and fibroblasts is enhanced by interleukin-1 and tumour necrosis factor-α.: Effects dependent on activation of NF-κB and MAP kinases
Kinin B1 and B2 receptor expression in osteoblasts and fibroblasts is enhanced by interleukin-1 and tumour necrosis factor-α.: Effects dependent on activation of NF-κB and MAP kinases
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DOI：
10.1016/j.bone.2008.02.003
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发表时间：
2008-07-01
期刊：
影响因子：
4.1
通讯作者：
Lerner, Ulf H.
中科院分区：
文献类型：
--
作者：
Brechter, Anna Bernhold;Persson, Emma;Lerner, Ulf H.
激肽释放酶 - 激肽系统形成的促炎介质能够刺激骨吸收，并协同增强由白细胞介素 -1（IL -1）和肿瘤坏死因子 -α（TNF -α）诱导的骨吸收。我们已经表明，这种效应与核因子 -κB受体活化因子配体（RANKL）表达的协同增强以及前列腺素生物合成的增强有关，这是由于环氧合酶 -2表达增加所致。在本研究中，我们研究了亲骨细胞因子和不同激肽对缓激肽（BK）、去精氨酸¹⁰ - 赖氨酸 - 缓激肽（DALBK）、白细胞介素 -1β和肿瘤坏死因子 -α受体亚型表达的影响。白细胞介素 -1β和肿瘤坏死因子 -α增强了人成骨细胞系MG -63中激肽B1和B2受体的结合，以及MG -63细胞、人牙龈成纤维细胞和完整小鼠颅骨中B1和B2受体的mRNA表达。激肽不影响白细胞介素 -1或肿瘤坏死因子受体的mRNA表达。电泳迁移率变动分析（EMSA）表明，白细胞介素 -1β和肿瘤坏死因子 -α激活了MG -63细胞中的核因子 -κB和激活蛋白 -1（AP -1）。白细胞介素 -1β通过非经典途径（p52 / p65）刺激核因子 -κB，肿瘤坏死因子 -α通过经典途径（p50 / p65）刺激核因子 -κB。激活蛋白 -1的激活在白细胞介素 -1β和肿瘤坏死因子 -α刺激的细胞中都涉及c - Jun，但c - Fos仅在肿瘤坏死因子 -α刺激的细胞中涉及。磷酸化酶联免疫吸附测定（Phospho - ELISA）和蛋白质印迹分析表明，白细胞介素 -1β激活了c - Jun氨基末端激酶（JNK）和p38，但不激活细胞外调节蛋白激酶1/2（ERK 1/2）丝裂原活化蛋白激酶。药理学抑制剂表明，核因子 -κB、p38和JNK对白细胞介素 -1β诱导的B1受体刺激很重要，核因子 -κB和p38对B2受体很重要。p38和JNK对肿瘤坏死因子 -α诱导的B1受体刺激很重要，而核因子 -κB、p38和JNK参与肿瘤坏死因子 -α诱导的B2受体表达。这些数据表明，白细胞介素 -1β和肿瘤坏死因子 -α通过涉及核因子 -κB和丝裂原活化蛋白激酶途径激活的机制上调B1和B2受体表达，但白细胞介素 -1β和肿瘤坏死因子 -α的信号转导途径不同。由促炎细胞因子白细胞介素 -1β和肿瘤坏死因子 -α诱导的激肽受体表达增强可能是激肽与两种细胞因子中的一种共同处理时前列腺素形成协同增强所涉及的一个重要机制。这些机制可能有助于解释与炎症性疾病（包括牙周炎和类风湿性关节炎）相关的骨吸收增强。（C）2008爱思唯尔公司。保留所有权利。
Pro-inflammatory mediators formed by the kallikrein-kinin system can stimulate bone resorption and synergistically potentiate bone resorption induced by IL-1 and TNF-alpha. We have shown that the effect is associated with synergistically enhanced RANKL expression and enhanced prostaglandin biosynthesis, due to increased cyclooxygenase-2 expression. In the present study, the effects of osteotropic cytokines and different kinins on the expression of receptor subtypes for bradykinin (BK), des-Arg(10)-Lys-BK (DALBK), IL-1 beta and TNF-alpha have been investigated. IL-1 beta and TNF-alpha enhanced kinin B1 and B2 receptor binding in the human osteoblastic cell line MG-63 and the mRNA expression of B1 and B2 receptors in MG-63 cells, human gingival fibroblasts and intact mouse calvarial bones. Kinins did not affect mRNA expression of IL-1 or TNF receptors. EMSA showed that IL-1 beta and TNF-alpha activated NF-kappa B and AP-1 in MG-63 cells. IL-1 beta stimulated NF-kappa B via a non-canonical pathway (p52/p65) and TNF-alpha via the canonical pathway (p50/p65). Activation of AP-1 involved c-Jun in both IL-1 beta and TNF-alpha stimulated cells, but c-Fos only in TNF-alpha stimulated cells. Phospho-ELISA and Western blots showed that IL-1 beta activated JNK and p38, but not ERK 1/2 MAP kinase. Pharmacological inhibitors showed that NF-kappa B, p38 and JNK were important for IL-1 beta induced stimulation of B1 receptors, and NF-kappa B and p38 for B2 receptors. p38 and JNK were important for TNF-alpha induced stimulation of B1 receptors, whereas NF-kappa B, p38 and JNK were involved in TNF-alpha induced expression of B2 receptors. These data show that IL-1 beta and TNF-alpha upregulate B1 and B2 receptor expression by mechanisms involving activation of both NF-kappa B and MAP kinase pathways, but that signal transduction pathways are different for IL-1 beta and TNF-alpha. The enhanced kinin receptor expression induced by the pro-inflammatory cytokines IL-1 beta and TNF-alpha might be one important mechanism involved in the synergistic enhancement of prostaglandin formation caused by co-treatment with kinins and one of the two cytokines. These mechanisms might help to explain the enhanced bone resorption associated with inflammatory disorders, including periodontitis and rheumatoid arthritis. (C) 2008 Elsevier Inc. All rights reserved.