title: A complex interaction between Rickettsia conorii and Dickkopf-1--potential role in immune evasion mechanisms in endothelial cells.
abstract: The pathophysiological hallmark of spotted fever group rickettsioses comprises vascular inflammation. Based on the emerging importance of the wingless (Wnt) pathways in inflammation and vascular biology, we hypothesized that Dickkopf-1 (DKK-1), as a major modulator of Wnt signaling, could be involved in the pathogenesis in rickettsial infections. Our major findings were: (i) While baseline concentration of DKK-1 in patients with R. conorii infection (n = 32) were not different from levels in controls (n = 24), DKK-1 rose significantly from presentation to first follow-up sample (median 7 days after baseline). (ii) In vitro experiments in human umbilical vein endothelial cells (HUVECs) showed that while heat-inactivated R. conorii enhanced the release of interleukin-6 (IL-6) and IL-8, it down-regulated the release of endothelial-derived DKK-1 in a time- and dose-dependent manner. (iii) Silencing of DKK-1 attenuated the release of IL-6, IL-8 and growth-related oncogene (GRO)α in R. conorii-exposed HUVECs, suggesting inflammatory effects of DKK-1. (iv) Silencing of DKK-1 attenuated the expression of tissue factor and enhanced the expression of thrombomodulin in R. conorii-exposed HUVECs suggesting pro-thrombotic effects of DKK-1. The capacity of R. conorii to down-regulate endothelial-derived DKK-1 and the ability of silencing DKK-1 to attenuate R. conorii-induced inflammation in endothelial cells could potentially reflect a novel mechanism by which R. conorii escapes the immune response at the site of infection.
authors.affiliation: Institute of Clinical Medicine, Akershus University Hospital, Lørenskog, Norway. Elisabeth.Astrup.Strand@rr-research.no
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Astrup
authors.forename: Tove
authors.initials: T
authors.lastname: Lekva
authors.forename: Giovanni
authors.initials: G
authors.lastname: Davì
authors.forename: Kari
authors.initials: K
authors.lastname: Otterdal
authors.forename: Francesca
authors.initials: F
authors.lastname: Santilli
authors.forename: Erik
authors.initials: E
authors.lastname: Oie
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
authors.forename: Jan Kristian
authors.initials: JK
authors.lastname: Damås
authors.forename: Didier
authors.initials: D
authors.lastname: Raoult
authors.forename: Giustina
authors.initials: G
authors.lastname: Vitale
authors.forename: Juan P
authors.initials: JP
authors.lastname: Olano
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001907:Boutonneuse Fever / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D016022:Case-Control Studies; D002460:Cell Line; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D005260:Female; D020868:Gene Silencing; D061307:Human Umbilical Vein Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D057131:Immune Evasion; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020114:Rickettsia conorii / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D055815:Young Adult
chemical_list: D016207:Cytokines; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D051153:Wnt Proteins