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 burdorferi, and is c haracterized by bacterial persistence and inflammation in a number of host tissues. B. burgdorferi outer surface lipoproteins possess cytoki ne stimulatory properties that may be responsible for localized inflam mation. 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 endo thelium, suggesting endothelial cells may participate in the inflammat ion of Lyme disease. In this study, outer surface protein A (OspA), a model B. burgdorferi lipoprotein, was found to be a potent stimulant o f nuclear factor-kappa B (NF-kappa B) nuclear translocation in human e ndothelial cells, resulting in nuclear levels similar to those seen in response to known inflammatory mediators. Only the lipid-modified Osp A had activity, and activity was not due to contamination with LPS, Nu clear NF-kappa B was detectable within 15 min, suggesting that OspA di rectly mediates NF-kappa B nuclear translocation. OspA also rapidly up -regulated endothelial cell production of several proteins whose trans cription 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 a dhesion 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 fo r localized inflammation via the direct activation of NF-kappa B-depen dent 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.