Induction of HO-1 on endothelial cells via PI3K signaling pathway by anti-NS1 antibodies in dengue virus infected patients
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Dengue haemorrhagic fever (DHF) is characterized by thrombocytopenia,increased vascular permeability and haemorrhage. The antibody against NS1 ofthe dengue virus seems to play a role in the pathogenesis of dengue virusdisease due to its cross-reaction with endothelial cells. Recently, it has beendemonstrated that anti-NS1 antibodies induced endothelial cells to undergo cellapoptosis. However, the exact mechanism underlying this antibody-mediated cellapoptosis is not well-known.In this study, the influence of anti-NS1 antibodies of DHF patients on theregulation of HO-1 in HUVEC was investigated. Sera derived from DHF patientswith or without anti-NS1 antibodies were analyzed. Incubation of HUVEC withpurified anti-NS1 antibodies from dengue virus infected patients caused HO-1upregulation in a time and dose manner which was attenuated by the NS1antigen. This upregulation was not observed with IgG from patients without NS1antibodies. Furthermore, reduction of HO-1 was observed, when HUVEC werepretreated with pI3K pathway inhibitors (LY294002 and wortmannin) prior tostimulation with anti-NS1 antibodies. In contrast, no inhibition was detectablewith p38 MAPK inhibitors (SB203580). These results indicate that the pI3Ksignaling pathway plays a major regulatory role for the induction of HO-1 by anti-NS1.In addition, stimulation of HUVEC with anti-NS1 antibodies induced theproduction of ROS, induced endothelial cell apoptosis, and increased cellpermeability. These mechanisms probably contribute to the pathomechanism ofvascular leakage and haemorrhage, which is often clinically observed in denguefever patients.Protein disulfide isomerase (PDI) was found expressed on the endothelialsurface as a target antigen for anti-NS1 antibodies by the use ofimmunoprecipitation approaches and flow cytometry analysis.Taken together, this study indicates that anti-NS1 antibodies bind to endothelialcells via PDI as a surface target protein. This interaction leads to production ofROS which can induce cell apoptosis and disturbance of endothelial cellpermeability. On the other hand, ROS initiates the induction of the anti-apoptoticgene HO-1 via the pI3K signalling pathway. Thus, the balance between ROS(apoptotic) and HO-1 (anti-apoptotic) production induced by anti-NS1 antibodiesmay have significance as the cause of vascular leakage in some DHF patients.Verknüpfung zu Publikationen oder weiteren Datensätzen
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Giessen : VVB Laufersweiler