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 (1×10cells/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.