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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-51064

Kahlenberg, J M; Thacker, S G; Berthier , C C; Cohen, C D; Kretzler, M; Kaplan, M J (2011). Activation of innate immune defense mechanisms contributes to polyomavirus BK-associated nephropathy. Journal of Immunology, 187(11):6143-6156.

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Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with heterogeneous manifestations including severe organ damage
and vascular dysfunction leading to premature atherosclerosis. IFN-a has been proposed to have an important role in the
development of lupus and lupus-related cardiovascular disease, partly by repression of IL-1 pathways leading to impairments
in vascular repair induced by endothelial progenitor cells (EPCs) and circulating angiogenic cells (CACs). Counterintuitively, SLE
patients also display transcriptional upregulation of the IL-1b/IL-18 processing machinery, the inflammasome. To understand this
dichotomy and its impact on SLE-related cardiovascular disease, we examined cultures of human and murine control or lupus
EPC/CACs to determine the role of the inflammasome in endothelial differentiation. We show that caspase-1 inhibition improves
dysfunctional SLE EPC/CAC differentiation into mature endothelial cells and blocks IFN-a–mediated repression of this differentiation,
implicating inflammasome activation as a crucial downstream pathway leading to aberrant vasculogenesis. Furthermore,
serum IL-18 levels are elevated in SLE and correlate with EPC/CAC dysfunction. Exogenous IL-18 inhibits endothelial
differentiation in control EPC/CACs and neutralization of IL-18 in SLE EPC/CAC cultures restores their capacity to differentiate
into mature endothelial cells, supporting a deleterious effect of IL-18 on vascular repair in vivo. Upregulation of the inflammasome
machinery was operational in vivo, as evidenced by gene array analysis of lupus nephritis biopsies. Thus, the effects of IFN-a
are complex and contribute to an elevated risk of cardiovascular disease by suppression of IL-1b pathways and by upregulation of
the inflammasome machinery and potentiation of IL-18 activation.

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28 citations in Web of Science®
28 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Nephrology
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
DDC:570 Life sciences; biology
610 Medicine & health
Date:2011
Deposited On:18 Nov 2011 07:32
Last Modified:22 Dec 2013 14:15
Publisher:American Association of Immunologists
ISSN:0022-1767
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.4049/jimmunol.1101284
PubMed ID:22058412

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