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 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.
Institute of Applied Biotechnology and Basic Sciences, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland; Centre of Applied Biotechnology and Basic Sciences, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland. Electronic address: jennifermytych@gmail.com.
Jennifer
J
Mytych
Institute of Applied Biotechnology and Basic Sciences, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland; Centre of Applied Biotechnology and Basic Sciences, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland.
Maria
M
Romerowicz-Misielak
Institute of Applied Biotechnology and Basic Sciences, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland; Centre of Applied Biotechnology and Basic Sciences, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland.
Marek
M
Koziorowski
D002118:Calcium / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D015032:Zinc; D002118:Calcium
Apoptosis; Cytotoxicity; Genotoxicity; LPS; Monocytes; Premature senescence