Minocycline ameliorates LPS-induced inflammation in human monocytes by novel mechanisms including LOX-1, Nur77 and LITAF inhibition.
Minocycline ameliorates LPS-induced inflammation in human monocytes by novel mechanisms including LOX-1, Nur77 and LITAF inhibition.
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DOI：
10.1016/j.bbagen.2012.01.011
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发表时间：
2012-04
影响因子：
3
通讯作者：
Saavedra, Juan M.
中科院分区：
文献类型：
--
作者：
Pang, Tao;Wang, Juan;Benicky, Julius;Saavedra, Juan M.
米诺环素具有独立于其抗生素活性的抗炎特性，可改善单核细胞和巨噬细胞的炎症反应。然而，米诺环素的抗炎作用机制尚不完全清楚。人外周血单核细胞在含脂多糖(LPS)、50 ng/ml和米诺环素(10-40µM)的条件下培养。用RT-PCR法检测基因表达，用ELISA法检测细胞因子和前列腺素E2(PGE2)的释放，用Western blotting检测蛋白表达、磷酸化和核转位。米诺环素可显著降低单核细胞的炎症反应，减少内毒素诱导的促炎性肿瘤坏死因子α(α)、白介素1β(IL-1β)、白介素6(IL-6)和环氧合酶-2(COX-2)的转录，减少内毒素刺激的单核细胞释放肿瘤坏死因子-α、白介素6和前列腺素E_2。米诺环素抑制脂多糖诱导的凝集素样氧化型低密度脂蛋白受体-1(LOX-1)、核因子-κB、脂多糖诱导的肿瘤坏死因子-α因子(LITAF)和核受体Nur77的激活。米诺环素的抗炎作用机制包括抑制脂多糖刺激的p38丝裂原活化蛋白激酶(P38MAPK)的激活和刺激磷脂酰肌醇3-激酶(PI3K)/Akt通路。我们提供了新的证据表明，米诺环素在人单核细胞中的抗炎作用包括，除了减少NF-κB的激活外，还取消了脂多糖刺激的LOX-1、LITAF、Nur77通路，抑制了p38MAPK，激活了PI3K/Akt。我们的结果显示，米诺环素抑制不同和相互作用的信号通路的汇聚点，介导多种炎症信号，这些信号可能影响单核细胞的激活、运输和向脑内的募集。我们在原代人类单核细胞上的研究结果有助于解释米诺环素在心血管和神经疾病中的深刻抗炎和保护作用，并可能具有直接的翻译相关性。
Minocycline exhibits anti-inflammatory properties independent of its antibiotic activity, ameliorating inflammatory responses in monocytes and macrophages. However, the mechanisms of minocycline anti-inflammatory effects are only partially understood. Human circulating monocytes were cultured in the presence of lipopolysaccharide (LPS), 50 ng/ml, and minocycline (10–40 µM). Gene expression was determined by RT-PCR, cytokine and prostaglandin E2 (PGE2) release by ELISA, protein expression, phosphorylation and nuclear translocation by Western blotting. Minocycline significantly reduced the inflammatory response in LPS-challenged monocytes, decreasing LPS-induced transcription of pro-inflammatory tumor-necrosis factor alpha (TNF-α), interleukin-1 beta, interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2), and the LPS-stimulated TNF-α, IL-6 and PGE2 release. Minocycline inhibited LPS-induced activation of the lectin-like oxidized low density lipoprotein receptor-1 (LOX-1), NF-κB, LPS-induced TNF-α factor (LITAF) and the Nur77 nuclear receptor. Mechanisms involved in the anti-inflammatory effects of minocycline include a reduction of LPS-stimulated p38 mitogen-activated protein kinase (p38 MAPK) activation and stimulation of the phosphoinositide 3-kinase (PI3K)/Akt pathway. We provide novel evidence demonstrating that the anti-inflammatory effects of minocycline in human monocytes include, in addition to decreased NF-κB activation, abrogation of the LPS-stimulated LOX-1, LITAF, Nur77 pathways, p38 MAPK inhibition and PI3K/Akt activation. Our results reveal that minocycline inhibits points of convergence of distinct and interacting signaling pathways mediating multiple inflammatory signals which may influence monocyte activation, traffic and recruitment into the brain. Our results in primary human monocytes contribute to explain the profound anti-inflammatory and protective effects of minocycline in cardiovascular and neurological diseases and may have direct translational relevance.
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影响因子：
4.9
作者：
Larrayoz IM;Pang T;Benicky J;Pavel J;Sánchez-Lemus E;Saavedra JM
通讯作者：
Saavedra JM
LITAF 介导发炎的结肠固有层巨噬细胞 TNF-α 分泌增加。
影响因子：
3.7
作者：
Bushell KN;Leeman SE;Gillespie E;Gower AC;Reed KL;Stucchi AF;Becker JM;Amar S
通讯作者：
Amar S
影响因子：
29
作者：
Baker RG;Hayden MS;Ghosh S
通讯作者：
Ghosh S
影响因子：
--
作者：
Pei, LM;Castrillo, A;Tontonoz, P
通讯作者：
Tontonoz, P
影响因子：
2.3
作者：
Noble, Wendy;Garwood, Claire J.;Hanger, Diane P.
通讯作者：
Hanger, Diane P.