Long-term culture with lipopolysaccharide induces dose-dependent cytostatic and cytotoxic effects in THP-1 monocytes

Monocytes act as a first line of defence against invading pathogens and their dysfunctions seem to be a key factor in many immune disorders. However, the data on mechanisms underlying these dysfunctions remain elusive. In this study, we evaluated the effects of long-term (168h) lipopolysaccharide ex...

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Veröffentlicht in:Toxicology in vitro 2017-08, Vol.42, p.1-9
Hauptverfasser: Mytych, Jennifer, Romerowicz-Misielak, Maria, Koziorowski, Marek
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Koziorowski, Marek
description Monocytes act as a first line of defence against invading pathogens and their dysfunctions seem to be a key factor in many immune disorders. However, the data on mechanisms underlying these dysfunctions remain elusive. In this study, we evaluated the effects of long-term (168h) lipopolysaccharide exposure on monocytes at low density cultures (1×105cells/ml). Treatment with low dose LPS (≤5μg/ml) resulted in oxidative stress induction followed by p21 pathway activation, permanent cell cycle arrest and SASP development. Furthermore, high dose LPS (≥10μg/ml) induced cell death involving mitochondrial pathways, death receptors as well as p21-dependent DNA damage response activation mediated by ROS generation and TNF-α release. Additionally, exposure to high dose of LPS resulted in THP-1 monocytes differentiation to macrophages. In conclusion, long-term culture with LPS exerts in low density monocytes cytostatic/cytotoxic effects in a dose-dependent manner by inducing senescence associated with chronic inflammation at low doses and initiation of cell death at higher doses. These findings shed new light on understanding of monocytes dysfunction, an issue relevant to chronic inflammation and many immune disorders. [Display omitted] •Monocyte dysfunctions are a key factor in many immune disorders.•LPS affects monocytes at low density cultures in a dose-dependent manner.•Low-dose LPS induces oxidative stress and permanent cell cycle arrest.•High-dose LPS induces apoptosis mediated by ROS generation and TNF-α release.•High-dose LPS induces THP-1 differentiation to macrophages.
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However, the data on mechanisms underlying these dysfunctions remain elusive. In this study, we evaluated the effects of long-term (168h) lipopolysaccharide exposure on monocytes at low density cultures (1×105cells/ml). Treatment with low dose LPS (≤5μg/ml) resulted in oxidative stress induction followed by p21 pathway activation, permanent cell cycle arrest and SASP development. Furthermore, high dose LPS (≥10μg/ml) induced cell death involving mitochondrial pathways, death receptors as well as p21-dependent DNA damage response activation mediated by ROS generation and TNF-α release. Additionally, exposure to high dose of LPS resulted in THP-1 monocytes differentiation to macrophages. In conclusion, long-term culture with LPS exerts in low density monocytes cytostatic/cytotoxic effects in a dose-dependent manner by inducing senescence associated with chronic inflammation at low doses and initiation of cell death at higher doses. These findings shed new light on understanding of monocytes dysfunction, an issue relevant to chronic inflammation and many immune disorders. [Display omitted] •Monocyte dysfunctions are a key factor in many immune disorders.•LPS affects monocytes at low density cultures in a dose-dependent manner.•Low-dose LPS induces oxidative stress and permanent cell cycle arrest.•High-dose LPS induces apoptosis mediated by ROS generation and TNF-α release.•High-dose LPS induces THP-1 differentiation to macrophages.</description><identifier>ISSN: 0887-2333</identifier><identifier>EISSN: 1879-3177</identifier><identifier>DOI: 10.1016/j.tiv.2017.03.009</identifier><identifier>PMID: 28341289</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Apoptosis ; Calcium - metabolism ; Cell activation ; Cell culture ; Cell cycle ; Cell Cycle Checkpoints - drug effects ; Cell death ; Cell Death - drug effects ; Cell Differentiation - drug effects ; Cell Line, Tumor ; Cell Survival - drug effects ; Cyclin-dependent kinase inhibitor p21 ; Cytotoxicity ; Death receptors ; Density ; Deoxyribonucleic acid ; Disorders ; DNA ; DNA damage ; DNA Fragmentation ; Erythrocytes ; Exposure ; Genotoxicity ; Humans ; Inflammation ; Lipopolysaccharides ; Lipopolysaccharides - pharmacology ; LPS ; Macrophages ; Mitochondria ; Mitochondrial DNA ; Monocytes ; Monocytes - drug effects ; Monocytes - metabolism ; Monocytes - physiology ; Mortality ; Oxidative stress ; Oxidative Stress - drug effects ; Phagocytosis - drug effects ; Premature senescence ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Receptors ; Senescence ; Tumor Necrosis Factor-alpha - metabolism ; Tumor necrosis factor-α ; Zinc - metabolism</subject><ispartof>Toxicology in vitro, 2017-08, Vol.42, p.1-9</ispartof><rights>2017 Elsevier Ltd</rights><rights>Copyright © 2017 Elsevier Ltd. 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However, the data on mechanisms underlying these dysfunctions remain elusive. In this study, we evaluated the effects of long-term (168h) lipopolysaccharide exposure on monocytes at low density cultures (1×105cells/ml). Treatment with low dose LPS (≤5μg/ml) resulted in oxidative stress induction followed by p21 pathway activation, permanent cell cycle arrest and SASP development. Furthermore, high dose LPS (≥10μg/ml) induced cell death involving mitochondrial pathways, death receptors as well as p21-dependent DNA damage response activation mediated by ROS generation and TNF-α release. Additionally, exposure to high dose of LPS resulted in THP-1 monocytes differentiation to macrophages. In conclusion, long-term culture with LPS exerts in low density monocytes cytostatic/cytotoxic effects in a dose-dependent manner by inducing senescence associated with chronic inflammation at low doses and initiation of cell death at higher doses. These findings shed new light on understanding of monocytes dysfunction, an issue relevant to chronic inflammation and many immune disorders. [Display omitted] •Monocyte dysfunctions are a key factor in many immune disorders.•LPS affects monocytes at low density cultures in a dose-dependent manner.•Low-dose LPS induces oxidative stress and permanent cell cycle arrest.•High-dose LPS induces apoptosis mediated by ROS generation and TNF-α release.•High-dose LPS induces THP-1 differentiation to macrophages.</description><subject>Apoptosis</subject><subject>Calcium - metabolism</subject><subject>Cell activation</subject><subject>Cell culture</subject><subject>Cell cycle</subject><subject>Cell Cycle Checkpoints - drug effects</subject><subject>Cell death</subject><subject>Cell Death - drug effects</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Cyclin-dependent kinase inhibitor p21</subject><subject>Cytotoxicity</subject><subject>Death receptors</subject><subject>Density</subject><subject>Deoxyribonucleic acid</subject><subject>Disorders</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA Fragmentation</subject><subject>Erythrocytes</subject><subject>Exposure</subject><subject>Genotoxicity</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Lipopolysaccharides</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>LPS</subject><subject>Macrophages</subject><subject>Mitochondria</subject><subject>Mitochondrial DNA</subject><subject>Monocytes</subject><subject>Monocytes - drug effects</subject><subject>Monocytes - metabolism</subject><subject>Monocytes - physiology</subject><subject>Mortality</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>Phagocytosis - drug effects</subject><subject>Premature senescence</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Receptors</subject><subject>Senescence</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Tumor necrosis factor-α</subject><subject>Zinc - metabolism</subject><issn>0887-2333</issn><issn>1879-3177</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEFPGzEQha2KqgmBH9ALssR5t-P1Zm2rJ4RoUykSHNKztdjj4ihZL7Y3NP--pqEcexo9zXtvNB8hnxnUDFj3ZVtnf6gbYKIGXgOoD2TOpFAVZ0KckTlIKaqGcz4j5yltAWApG_hEZo3kLWukmpO8DsOvKmPcUzPt8hSRvvj8RHd-DGPYHVNvzFMfvUXqBzsZTNSGhJXFEQeLQ6bmmEPKffaG9oP9K3P4XRQ6hyankqOb1UPF6D4MoawxXZCPrt8lvHybC_Lz293mdlWt77__uL1ZV4ZLlqtH6VrOAJy0YFzfYsc6NJ1ABU4tO2ZMb4tqrFEM20a0nXASXMsUCtUuJV-Q61PvGMPzhCnrbZjiUE7qBiSXoCSI4mInl4khpYhOj9Hv-3jUDPQrZ73VhbN-5ayB68K5ZK7emqfHPdr3xD-wxfD1ZMDy38Fj1Ml4HAxaHwsVbYP_T_0fjl-PvQ</recordid><startdate>201708</startdate><enddate>201708</enddate><creator>Mytych, Jennifer</creator><creator>Romerowicz-Misielak, Maria</creator><creator>Koziorowski, Marek</creator><general>Elsevier Ltd</general><general>Elsevier Science Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>201708</creationdate><title>Long-term culture with lipopolysaccharide induces dose-dependent cytostatic and cytotoxic effects in THP-1 monocytes</title><author>Mytych, Jennifer ; 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These findings shed new light on understanding of monocytes dysfunction, an issue relevant to chronic inflammation and many immune disorders. [Display omitted] •Monocyte dysfunctions are a key factor in many immune disorders.•LPS affects monocytes at low density cultures in a dose-dependent manner.•Low-dose LPS induces oxidative stress and permanent cell cycle arrest.•High-dose LPS induces apoptosis mediated by ROS generation and TNF-α release.•High-dose LPS induces THP-1 differentiation to macrophages.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>28341289</pmid><doi>10.1016/j.tiv.2017.03.009</doi><tpages>9</tpages></addata></record>
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subjects Apoptosis
Calcium - metabolism
Cell activation
Cell culture
Cell cycle
Cell Cycle Checkpoints - drug effects
Cell death
Cell Death - drug effects
Cell Differentiation - drug effects
Cell Line, Tumor
Cell Survival - drug effects
Cyclin-dependent kinase inhibitor p21
Cytotoxicity
Death receptors
Density
Deoxyribonucleic acid
Disorders
DNA
DNA damage
DNA Fragmentation
Erythrocytes
Exposure
Genotoxicity
Humans
Inflammation
Lipopolysaccharides
Lipopolysaccharides - pharmacology
LPS
Macrophages
Mitochondria
Mitochondrial DNA
Monocytes
Monocytes - drug effects
Monocytes - metabolism
Monocytes - physiology
Mortality
Oxidative stress
Oxidative Stress - drug effects
Phagocytosis - drug effects
Premature senescence
Reactive oxygen species
Reactive Oxygen Species - metabolism
Receptors
Senescence
Tumor Necrosis Factor-alpha - metabolism
Tumor necrosis factor-α
Zinc - metabolism
title Long-term culture with lipopolysaccharide induces dose-dependent cytostatic and cytotoxic effects in THP-1 monocytes
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