Identification of Signaling Pathways Mediating Cell Cycle Arrest and Apoptosis Induced by Porphyromonas gingivalis in Human Trophoblasts

Abstract

Epidemiological and interventional studies of humans have revealed a close association between periodontal diseases and preterm delivery of low-birth-weight infants. Porphyromonas gingivalis, a periodontal pathogen, can translocate to gestational tissues following oral-hematogenous spread. We previously reported that P. gingivalis invades extravillous trophoblast cells (HTR-8) derived from the human placenta and inhibits proliferation through induction of arrest in the G(1) phase of the cell cycle. The purpose of the present study was to identify signaling pathways mediating cellular impairment caused by P. gingivalis. Following P. gingivalis infection, the expression of Fas was induced and p53 accumulated, responses consistent with response to DNA damage. Ataxia telangiectasia- and Rad3-related kinase (ATR), an essential regulator of DNA damage checkpoints, was shown to be activated together with its downstream signaling molecule Chk2, while the p53 degradation-related protein MDM2 was not induced. The inhibition of ATR prevented both G(1) arrest and apoptosis caused by P. gingivalis in HTR-8 cells. In addition, small interfering RNA (siRNA) knockdown of p53 abrogated both G(1) arrest and apoptosis. The regulation of apoptosis was associated with Ets1 activation. HTR-8 cells infected with P. gingivalis exhibited activation of Ets1, and knockdown of Ets1 with siRNA diminished both G(1) arrest and apoptosis. These results suggest that P. gingivalis activates cellular DNA damage signaling pathways that lead to G(1) arrest and apoptosis in trophoblasts.