Protective role of klotho protein on epithelial cells upon co-culture with activated or senescent monocytes

•Activated and senescent THP-1 monocytes induced cyto- and genotoxicity in HeLa cells.•Altered monocytes provoked oxidative and nitrosative stress-induced DNA damage.•DNA damage activated DDR pathways and lead to premature senescence and apoptosis.•Klotho reduced ROS/RNS-mediated toxicity through insulin/IGF-IR pathway inhibition.•Klotho protects HeLa cells from cyto- and genotoxicity induced by altered monocytes.

Monocytes ensure proper functioning and maintenance of epithelial cells, while good condition of monocytes is a key factor of these interactions. Although, it was shown that in some circumstances, a population of altered monocytes may appear, there is no data regarding their effect on epithelial cells. In this study, using direct co-culture model with LPS-activated and Dox-induced senescent THP-1 monocytes, we reported for the first time ROS-induced DNA damage, reduced metabolic activity, proliferation inhibition and cell cycle arrest followed by p16-, p21- and p27-mediated DNA damage response pathways activation, premature senescence and apoptosis induction in HeLa cells. Also, we show that klotho protein possessing anti-aging and anti-inflammatory characteristics reduced cytotoxic and genotoxic events by inhibition of insulin/IGF-IR and downregulation of TRF1 and TRF2 proteins. Therefore, klotho protein could be considered as a protective factor against changes caused by altered monocytes in epithelial cells.

Graphical abstractDownload high-res image (182KB)Download full-size image