Bartonella quintana-induced apoptosis inhibition of human endothelial cells is associated with p38 and SAPK/JNK modulation and with stimulation of mitosis.
Previous studies demonstrated that live Bartonella quintana often induces angioproliferative lesions in humans. It modulates endothelial cell apoptotic and inflammatory patterns, thus inducing a very early overexpression of caspase 8 and Apaf-1 and increasing mRNA production of TNF-alpha, interleukin-8, and E-selectin. However, starting at 10 hours postinfection, the bacteria provoke antiapoptotic effects that induce an increase of bcl-2 gene transcription. To gain further insight into the cellular mechanisms that regulate apoptosis, survival and proliferation, we studied the modulation of mitogen-activated protein kinase (MAPK) and the activation state of cdc2 kinase, which regulates progression into mitosis. Confocal microscopy findings indicated a maximum rate of Bartonella entry into host cells between postinfection hours 6 and 10. Live bacteria caused substantially higher apoptosis of human umbilical vein endothelial cells-cryopreserved (HUVEC-C) than heat- and trypsin-inactivated microorganisms. During the first 6 hours postinfection, B. quintana triggered a peak of apoptosis, induced activation of p38 MAPK and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), with bacterial clusters appearing at the cellular surface of the HUVEC-C. However, at 8 to 24 hours postinfection, B. quintana was internalized and inhibited proapoptotic signals such as p38 MAPK and SAPK/JNK while inducing antiapoptotic signals. Indeed, expression of the bcl-2 gene and the increase of the bcl-2 kinase active form was concomitant to activation of mitosis, as shown by cdc2 protein activation. These data thus suggest that mechanisms that induce mitotic activity and inhibit apoptotic signals may contribute to the ability of B. quintana to cause vascular proliferation.
Liberto
Maria Carla
MC
Institute of Microbiology, Department of Medical Sciences, University of Catanzaro, Catanzaro, Italy. mliberto@unicz.it
Matera
Giovanni
G
Lamberti
Angelo G
AG
Barreca
Giorgio S
GS
Focà
Domenico
D
Quirino
Angela
A
Soria
Marco R
MR
Focà
Alfredo
A
D017209:Apoptosis / Q000502:physiology*; D018413:Bartonella quintana / Q000472:pathogenicity*; D016203:CDC2 Protein Kinase / Q000502:physiology; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology* / Q000201:enzymology / Q000382:microbiology*; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000502:physiology; D019254:Genes, bcl-2 / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008938:Mitosis / Q000502:physiology*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016203:CDC2 Protein Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases