RGD Reference Report - The detrimental effects of IFN-alpha on vasculogenesis in lupus are mediated by repression of IL-1 pathways: potential role in atherogenesis and renal vascular rarefaction. - Rat Genome Database

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The detrimental effects of IFN-alpha on vasculogenesis in lupus are mediated by repression of IL-1 pathways: potential role in atherogenesis and renal vascular rarefaction.

Authors: Thacker, SG  Berthier, CC  Mattinzoli, D  Rastaldi, MP  Kretzler, M  Kaplan, MJ 
Citation: Thacker SG, etal., J Immunol. 2010 Oct 1;185(7):4457-69. Epub 2010 Aug 30.
RGD ID: 6906963
Pubmed: PMID:20805419   (View Abstract at PubMed)
PMCID: PMC2978924   (View Article at PubMed Central)
DOI: DOI:10.4049/jimmunol.1001782   (Journal Full-text)

Systemic lupus erythematosus (SLE) is characterized by increased vascular risk due to premature atherosclerosis independent of traditional risk factors. We previously proposed that IFN-alpha plays a crucial role in premature vascular damage in SLE. IFN-alpha alters the balance between endothelial cell apoptosis and vascular repair mediated by endothelial progenitor cells (EPCs) and myeloid circulating angiogenic cells (CACs). In this study, we demonstrate that IFN-alpha promotes an antiangiogenic signature in SLE and control EPCs/CACs, characterized by transcriptional repression of IL-1alpha and beta, IL-1R1, and vascular endothelial growth factor A, and upregulation of IL-1R antagonist and the decoy receptor IL-1R2. IL-1beta promotes significant improvement in the functional capacity of lupus EPCs/CACs, therefore abrogating the deleterious effects of IFN-alpha. The beneficial effects from IL-1 are mediated, at least in part, by increases in EPC/CAC proliferation, by decreases in EPC/CAC apoptosis, and by preventing the skewing of CACs toward nonangiogenic pathways. IFN-alpha induces STAT2 and 6 phosphorylation in EPCs/CACs, and JAK inhibition abrogates the transcriptional antiangiogenic changes induced by IFN-alpha in these cells. Immunohistochemistry of renal biopsies from patients with lupus nephritis, but not anti-neutrophil cytoplasmic Ab-positive vasculitis, showed this pathway to be operational in vivo, with increased IL-1R antagonist, downregulation of vascular endothelial growth factor A, and glomerular and blood vessel decreased capillary density, compared with controls. Our study introduces a novel putative pathway by which type I IFNs may interfere with vascular repair in SLE through repression of IL-1-dependent pathways. This could promote atherosclerosis and loss of renal function in this disease.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
IL1RNHumansystemic lupus erythematosus  IEP protein:increased expression:plasma (human)RGD 
Il1rnRatsystemic lupus erythematosus  ISOIL1RN (Homo sapiens)protein:increased expression:plasma (human)RGD 
Il1rnMousesystemic lupus erythematosus  ISOIL1RN (Homo sapiens)protein:increased expression:plasma (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Il1rn  (interleukin 1 receptor antagonist)

Genes (Mus musculus)
Il1rn  (interleukin 1 receptor antagonist)

Genes (Homo sapiens)
IL1RN  (interleukin 1 receptor antagonist)


Additional Information