A Complex Interaction between Rickettsia conorii and Dickkopf-1 - Potential Role in Immune Evasion Mechanisms in Endothelial Cells
Astrup, Elisabeth; Lekva, Tove; Davi, Giovanni; Otterdal, Kari; Santilli, Francesca; Øie, Erik; Halvorsen, Bente; Damås, Jan Kristian; Raoult, Didier; Vitale, Giustina; Olano, Juan P; Ueland, Thor; Aukrust, Pål
Journal article, Peer reviewed
Permanent lenke
http://hdl.handle.net/11250/2365403Utgivelsesdato
2012Metadata
Vis full innførselSamlinger
- Institutt for biologi [2604]
- Publikasjoner fra CRIStin - NTNU [38484]
Sammendrag
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 heatinactivated
R. conorii enhanced the release of interleukin-6 (IL-6) and IL-8, it down-regulated the release of endothelialderived
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)a 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.