Borrelia burgdorferi outer membrane protein A induces nuclear translocation of nuclear factor-kappa B and inflammatory activation in human endothelial cells.
Lyme disease is caused by infection with Borrelia burgdorferi, and is characterized by bacterial persistence and inflammation in a number of host tissues. B. burgdorferi outer surface lipoproteins possess cytokine stimulatory properties that may be responsible for localized inflammation. B. burgdorferi presence is correlated with severity of disease, and the pathology of many tissues, particularly the arthritic joint, is consistent with localized cytokine production. Spirochete invasion of tissues requires interaction with and penetration of vascular endothelium, suggesting endothelial cells may participate in the inflammation of Lyme disease. In this study, outer surface protein A (OspA), a model B. burgdorferi lipoprotein, was found to be a potent stimulant of nuclear factor-kappa B (NF-kappa B) nuclear translocation in human endothelial cells, resulting in nuclear levels similar to those seen in response to known inflammatory mediators. Only the lipid-modified OspA had activity, and activity was not due to contamination with LPS. Nuclear NF-kappa B was detectable within 15 min, suggesting that OspA directly mediates NF-kappa B nuclear translocation. OspA also rapidly up-regulated endothelial cell production of several proteins whose transcription is dependent on NF-kappa B: the cytokine IL-6; the chemokine IL-8; and the adhesion molecules E-selectin, VCAM-1, and ICAM-1. The adhesion molecules were functional, as demonstrated by enhanced binding of neutrophils to OspA-stimulated endothelial monolayers. These data suggest that OspA may initiate synthesis of many proteins essential for localized inflammation via the direct activation of NF-kappa B-dependent transcription. These observations suggest that the interaction of B. burgdorferi lipoproteins with the endothelium may directly induce the inflammation responsible for the symptoms of Lyme disease.
Department of Pathology, University of Utah Health Sciences Center, Salt Lake City 84132, USA.
R M
RM
Wooten
V R
VR
Modur
T M
TM
McIntyre
J J
JJ
Weis
D000954:Antigens, Surface / Q000032:analysis / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000032:analysis / Q000494:pharmacology*; D001428:Bacterial Vaccines; D001692:Biological Transport / Q000187:drug effects; D015748:Borrelia burgdorferi Group / Q000276:immunology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000276:immunology / Q000473:pathology*; D006801:Humans; D008074:Lipoproteins; D008193:Lyme Disease / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism*; D014471:Umbilical Veins
D000954:Antigens, Surface; D001425:Bacterial Outer Membrane Proteins; D001428:Bacterial Vaccines; D008074:Lipoproteins; D016328:NF-kappa B; C072045:OspA protein