Porphyromonas gingivalis invades human trophoblasts and inhibits proliferation by inducing G1 arrest and apoptosis.
Porphyromonas gingivalis is an oral pathogen that is also associated with serious systemic conditions such as preterm delivery. Here we investigated the interaction between P. gingivalis and a cell line of extravillous trophoblasts (HTR-8) derived from the human placenta. P. gingivalis internalized within HTR-8 cells and inhibited proliferation through induction of arrest in the G1 phase of the cell cycle. G1 arrest was associated with decreased expression of cyclin D and of CDKs 2, 4 and 6. In addition, levels of CDK inhibitors p15, p16, p18 and p21 were increased following P. gingivalis infection. The amount of Rb was diminished by P. gingivalis, and transient overexpression of Rb, with concomitant upregulation of phospho-Rb, relieved P. gingivalis-induced G1 arrest. HTR-8 cells halted in the G1 phase became apoptotic, and apoptosis was accompanied by an increase in the ratio of Bax/Bcl-2 and increased activity of caspases 3, 7 and 9. HTR-8 cells infected with P. gingivalis also exhibited a sustained activation of ERK1/2, and knock-down of ERK1/2 activity with siRNA abrogated both G1 arrest and apoptosis. Thus, P. gingivalis can invade placental trophoblasts and induce G1 arrest and apoptosis through pathways involving ERK1/2 and its downstream effectors, properties that provide a mechanistic basis for pathogenicity in complications of pregnancy.
Inaba
Hiroaki
H
Department of Oral Biology, College of Dentistry and Emerging Pathogens Institute, University of Florida, Gainesville, 32610, USA.
Kuboniwa
Masae
M
Bainbridge
Brian
B
Yilmaz
Ozlem
O
Katz
Joseph
J
Shiverick
Kathleen T
KT
Amano
Atsuo
A
Lamont
Richard J
RJ
D017209:Apoptosis; D020169:Caspases / Q000096:biosynthesis; D002453:Cell Cycle; D002460:Cell Line; D056741:Cyclin D; D051357:Cyclin-Dependent Kinase 2 / Q000096:biosynthesis; D051358:Cyclin-Dependent Kinase 4 / Q000096:biosynthesis; D051361:Cyclin-Dependent Kinase 6 / Q000096:biosynthesis; D016213:Cyclins / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression; D006801:Humans; D016966:Porphyromonas gingivalis / Q000472:pathogenicity*; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000382:microbiology; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D014327:Trophoblasts / Q000382:microbiology*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
C494826:BAX protein, human; D056741:Cyclin D; D016213:Cyclins; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein; D051028:bcl-2-Associated X Protein; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D020169:Caspases