title: Hepatitis C virus induced endothelial inflammatory response depends on the functional expression of TNFα receptor subtype 2.
abstract: In hepatitis C virus (HCV) infection, morbidity and mortality often result from extrahepatic disease manifestations. We provide evidence for a role of receptors of the innate immune system in virally induced inflammation of the endothelium in vitro and in vivo. Corresponding to the in vitro finding of an HCV-dependent induction of proinflammatory mediators in endothelial cells, mice treated with poly (I:C) exhibit a significant reduction in leukocyte rolling velocity, an increase in leukocyte adhesion to the vessel wall and an increased extravasation of leukocytes. HCV directly promotes activation, adhesion and infiltration of inflammatory cells into the vessel wall by activation of endothelial viral receptors. Poly (I:C) induces the expression of TLR3 in vivo and hereby allows for amplification of all of the aforementioned responses upon viral infection. Proinflammatory effects of viral RNA are specifically mediated by TLR3 and significantly enhanced by tumor necrosis factor alpha (TNFα). HCV-RNA induces the endothelial expression of TNFα and TNFα receptor subtype 2 and we provide evidence that leucocyte adhesion and transmigration in response to activation of viral RNA receptors seem to depend on expression of functional TNFR2. Our results demonstrate that endothelial cells actively participate in immune mediated vascular inflammation caused by viral infections.
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität München, München, Germany; Walter Brendel Centre of Experimental Medicine and Munich Heart Alliance, Ludwig Maximilians University München, München, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Pircher
authors.affiliation: Walter Brendel Centre of Experimental Medicine and Munich Heart Alliance, Ludwig Maximilians University München, München, Germany; Medizinische Klinik und Poliklinik IV, Innenstadt, Klinikum der Universität München, München, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Czermak
authors.affiliation: Medizinische Klinik und Poliklinik IV, Innenstadt, Klinikum der Universität München, München, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Merkle
authors.affiliation: Walter Brendel Centre of Experimental Medicine and Munich Heart Alliance, Ludwig Maximilians University München, München, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Mannell
authors.affiliation: Walter Brendel Centre of Experimental Medicine and Munich Heart Alliance, Ludwig Maximilians University München, München, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Krötz
authors.affiliation: Medizinische Klinik und Poliklinik IV, Innenstadt, Klinikum der Universität München, München, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ribeiro
authors.affiliation: Medizinische Klinik und Poliklinik IV, Innenstadt, Klinikum der Universität München, München, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Vielhauer
authors.affiliation: Medizinische Klinik und Poliklinik IV, Innenstadt, Klinikum der Universität München, München, Germany.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Nadjiri
authors.affiliation: Walter Brendel Centre of Experimental Medicine and Munich Heart Alliance, Ludwig Maximilians University München, München, Germany; Medizinische Klinik und Poliklinik IV, Innenstadt, Klinikum der Universität München, München, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Gaitzsch
authors.affiliation: Department of Gynecology, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Niemeyer
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Porubsky
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.affiliation: Medizinische Klinik und Poliklinik IV, Innenstadt, Klinikum der Universität München, München, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Wörnle
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000821:virology*; D015870:Gene Expression / Q000187:drug effects; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D036904:Leukocyte Rolling / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011070:Poly I-C / Q000494:pharmacology; D034622:RNA Interference; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D047889:Receptors, Tumor Necrosis Factor, Type II; C495344:TLR3 protein, human; C415902:TNFRSF1B protein, human; D051196:Toll-Like Receptor 3; D014409:Tumor Necrosis Factor-alpha; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C