Background/Purpose: While type I interferon
(IFN) has been linked to atherosclerosis progression in systemic lupus
erythematosus (SLE), little is known about its regulation and intervention. In this
study, we assessed the effect of IFN-alpha on several classic atherosclerosis
related factors, including macrophage migration inhibitory factor (MIF),
vascular endothelial growth factor (VEGF) and numbers of peripheral endothelial
progenitor cells (EPC), and explored the role of artesunate (ART), an
anti-malarial agent extracted from Chinese herbs, on this process.

Methods: Levels of MIF and VEGF in serum or
cultured supernatants were measured by ELISA, and numbers of peripheral EPC were
detected by flow cytometry. Their relationships with IFN scores that calculated
by 5 type I IFN gene (LY6E, OAS1, OASL, ISG15 and MX1) expression levels were
assessed by Spearman correlation analysis. ART at different concentrations was
added to human umbilical vein endothelial cells (HUVEC) cultures with or
without prior IFN- alpha 1b stimulation and to SLE peripheral blood mononuclear
cells (PBMC) cultures. To find out how ART regulated IFN signaling, the levels
of total and phosphorylated (p) STAT1, 3, 5 in cultured HUVECs were tested by
Western blot.

Results: Compared to age- and gender- matched
normal controls, SLE patients had lower EPC numbers, lower VEGF levels, but
higher MIF levels (all p < 0.0001). The reduction of EPC numbers and the increase of MIF levels were tightly correlated
with the elevation of IFN score in SLE patients (both p < 0.001). In
vitro cultures showed that HUVEC produced significantly higher amount of
MIF after IFN-alpha stimulation, while VEGF levels varied at different time
periods by showing a decline after 12 hours stimulation but an increase at 24
hours. ART at 20 µmol/L significantly suppressed IFN-alpha promoted VEGF and
MIF production at 24 hours, along with the dramatic decline of IFN inducible
gene expressions. Similar to that in HUVEC, ART treatment also inhibited VEGF
and MIF production in SLE PBMC cultures. As shown in Figure 1, over-expression
of p-STAT1, but not p-STAT3 or 5, was detected after IFN-alpha stimulation,
which was completely reversed at the presence of ART.

Conclusion: Our data supports a
potential role for type I IFN signaling in atherosclerosis. ART may
down-regulate IFN-alpha modulated pro-atherosclerotic factors through the
inhibition of STAT1 phosphorylation, thus could have therapeutic effect on
SLE-associated atherosclerosis.