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The Effect of Lithium on Inflammation-Associated Genes in Lipopolysaccharide-Activated Raw 264.7 Macrophages.

ABSTRACT: Lithium remains the preferred Food and Drug Administration- (FDA-) approved psychiatric drug for treatment of bipolar disorders since its medical establishment more than half a century ago. Recent studies revealed a promising role for lithium in the regulation of inflammation, oxidative stress, and neurodegeneration albeit unclear about its exact mode of action. Thus, the intention of this study is to delineate the regulatory mechanisms of lithium on oxidative stress in lipopolysaccharide- (LPS-) activated macrophages by evaluating its effects on nuclear factor-?B (NF-?B) activity and mRNA expression of multiple oxidative stress-related NF-?B genes. Raw 264.7 macrophages were treated with up to 10?mM lithium, and no change in cell proliferation, viability, growth, and cell adhesion was observed in real time. Pretreatment with low doses of lithium was shown to reduce nitric oxide (NO) production in LPS-activated macrophages. A reduced internal H2DCFDA fluorescence intensity, indicative of reduced reactive oxygen species (ROS) production, was observed in LPS-activated Raw 264.7 macrophages treated with lithium. Lithium has been shown to lower the production of the chemokine RANTES; furthermore, this inhibitory action of lithium has been suggested to be independent of glycogen synthase kinase-3 ? (GSK3?) activity. It is shown here that lithium modulates the expression of several inflammatory genes including I?B-?, TRAF3, Tollip, and NF-?B1/p50 which are regulators of the NF-?B pathway. Moreover, lithium inhibits NF-?B activity by lowering nuclear translocation of NF-?B in LPS-activated macrophages. This is the first study to associate Tollip, Traf-3, and I?B-? mRNA expression with lithium effect on NF-?B activity in LPS-activated Raw 264.7 macrophages. Although these effects were obtained using extratherapeutic concentrations of lithium, results of this study provide useful information towards understanding the mode of action of lithium. This study associates lithium with reduced oxidative stress in LPS-activated Raw 264.7 macrophages and further suggests candidate molecular targets for the regulation of oxidative stress-related diseases using lithium beyond bipolar disorders.

SUBMITTER: Makola RT

PROVIDER: S-EPMC7397420 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Effect of Lithium on Inflammation-Associated Genes in Lipopolysaccharide-Activated Raw 264.7 Macrophages.

Makola Raymond T RT Mbazima Vusi G VG Mokgotho Matlou P MP Gallicchio Vincent S VS Matsebatlela Thabe M TM

International journal of inflammation 20200725

Lithium remains the preferred Food and Drug Administration- (FDA-) approved psychiatric drug for treatment of bipolar disorders since its medical establishment more than half a century ago. Recent studies revealed a promising role for lithium in the regulation of inflammation, oxidative stress, and neurodegeneration <i>albeit</i> unclear about its exact mode of action. Thus, the intention of this study is to delineate the regulatory mechanisms of lithium on oxidative stress in lipopolysaccharide ...[more]

PMID: 32774832

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Project description:Hippophae rhamnoides L. (Elaeagnaceae; commonly known as "sea buckthorn" and "vitamin tree"), is a spiny deciduous shrub whose fruit is used in foods and traditional medicines. The H. rhamnoides fruit (berry) is rich in vitamin C, with a level exceeding that found in lemons and oranges. H. rhamnoides berries are usually washed and pressed to create pomace and juice. Today, the powder of the aqueous extract of H. rhamnoides berries are sold as a functional food in many countries. As part of our ongoing effort to identify bioactive constituents from natural resources, we aimed to isolate and identify those from the fruits of H. rhamnoides. Phytochemical analysis of the extract of H. rhamnoides fruits led to the isolation and identification of six compounds, namely, a citric acid derivative (1), a phenolic (2), flavonoids (3 and 4), and megastigmane compounds (5 and 6). Treatment with compounds 1-6 did not have any impact on the cell viability of RAW 264.7 mouse macrophages. However, pretreatment with these compounds suppressed lipopolysaccharide (LPS)-induced NO production in RAW 264.7 mouse macrophages in a concentration-dependent manner. Among the isolated compounds, compound 1 was identified as the most active, with an IC50 of 39.76 ± 0.16 μM. This value was comparable to that of the NG-methyl-L-arginine acetate salt, a nitric oxide synthase inhibitor with an IC50 of 28.48 ± 0.05 μM. Western blot analysis demonstrated that compound 1 inhibited the LPS-induced expression of IKKα/β (IκB kinase alpha/beta), I-κBα (inhibitor of kappa B alpha), nuclear factor kappa-B (NF-κB) p65, iNOS (inducible nitric oxide synthase), and COX-2 (cyclooxygenase-2) in RAW 264.7 cells. Furthermore, LPS-stimulated cytokine production was detected using a sandwich enzyme-linked immunosorbent assay. Compound 1 decreased interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) production in LPS-stimulated RAW 264.7 cells. In summary, the mechanism of action of 1 included the suppression of LPS-induced NO production in RAW 264.7 cells by inhibiting IKKα/β, I-κBα, NF-κB p65, iNOS, and COX-2, and the activities of IL-6 and TNF-α.

Dataset Information

The Effect of Lithium on Inflammation-Associated Genes in Lipopolysaccharide-Activated Raw 264.7 Macrophages.

Publications

The Effect of Lithium on Inflammation-Associated Genes in Lipopolysaccharide-Activated Raw 264.7 Macrophages.

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