Tao Pang1, Juan Wang, Julius Benicky, Juan M Saavedra. 1. Section on Pharmacology, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA. pangt@mail.nih.gov
Abstract
BACKGROUND: 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. METHODS: 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 E(2) (PGE(2)) release by ELISA, protein expression, phosphorylation and nuclear translocation by Western blotting. RESULTS: 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 PGE(2) 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. CONCLUSIONS: 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. GENERAL SIGNIFICANCE: 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. Published by Elsevier B.V.
BACKGROUND: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. METHODS: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 E(2) (PGE(2)) release by ELISA, protein expression, phosphorylation and nuclear translocation by Western blotting. RESULTS: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 PGE(2) 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. CONCLUSIONS: 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. GENERAL SIGNIFICANCE: 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. Published by Elsevier B.V.
Authors: Hai Ling Li; Jun Suzuki; Evelyn Bayna; Fu-Min Zhang; Erminia Dalle Molle; Aaron Clark; Robert L Engler; Wilbur Y W Lew Journal: Am J Physiol Heart Circ Physiol Date: 2002-08 Impact factor: 4.733
Authors: Ursula Bommhardt; Katherine C Chang; Paul E Swanson; Tracey H Wagner; Kevin W Tinsley; Irene E Karl; Richard S Hotchkiss Journal: J Immunol Date: 2004-06-15 Impact factor: 5.422
Authors: Christopher R Dunston; Helen R Griffiths; Peter A Lambert; Susan Staddon; Ann B Vernallis Journal: Proteomics Date: 2010-12-06 Impact factor: 3.984
Authors: Kristen N Bushell; Susan E Leeman; Earl Gillespie; Adam C Gower; Karen L Reed; Arthur F Stucchi; James M Becker; Salomon Amar Journal: PLoS One Date: 2011-09-30 Impact factor: 3.240
Authors: Zhengzi Yi; Karen L Keung; Li Li; Min Hu; Bo Lu; Leigh Nicholson; Elvira Jimenez-Vera; Madhav C Menon; Chengguo Wei; Stephen Alexander; Barbara Murphy; Philip J O'Connell; Weijia Zhang Journal: JCI Insight Date: 2020-08-06
Authors: Biswarup Ghosh; Jia Nong; Zhicheng Wang; Mark W Urban; Nicolette M Heinsinger; Victoria A Trovillion; Megan C Wright; Angelo C Lepore; Yinghui Zhong Journal: Neurobiol Dis Date: 2019-04-25 Impact factor: 5.996
Authors: K Kobayashi; S Imagama; T Ohgomori; K Hirano; K Uchimura; K Sakamoto; A Hirakawa; H Takeuchi; A Suzumura; N Ishiguro; K Kadomatsu Journal: Cell Death Dis Date: 2013-03-07 Impact factor: 8.469