PT  - JOURNAL ARTICLE
AU  - Giuseppina Farina
AU  - Michael York
AU  - Cindy Collins
AU  - Robert Lafyatis
TI  - dsRNA activation of endothelin-1 and markers of vascular activation in endothelial cells and fibroblasts
AID  - 10.1136/ard.2010.132464
DP  - 2011 Mar 01
TA  - Annals of the Rheumatic Diseases
PG  - 544--550
VI  - 70
IP  - 3
4099  - http://ard.bmj.com/content/70/3/544.short
4100  - http://ard.bmj.com/content/70/3/544.full
SO  - Ann Rheum Dis2011 Mar 01; 70
AB  - Background In patients with systemic sclerosis (SSc), the relationship between innate immune activation, represented by increased expression of interferon (IFN)-regulated genes, and vascular injury/activation, manifest by increased endothelin-1 (ET-1), endothelin converting enzyme-1 (ECE1) and intercellular adhesion molecule-1, is uncertain. Objective To investigate the potential roles of innate immune ligands in both these pathogenic pathways. Methods The effect of known Toll-like receptor (TLR) ligands was tested in vitro on dermal microvascular and pulmonary arterial endothelial cells, and on dermal fibroblasts cultured from healthy controls and patients with SSc. To test the effect of double-stranded RNA (dsRNA) on vascular activation/injury in vivo, polyinosinic/polycytidylic acid (poly(I:C)) was administered continuously over 7 days by subcutaneous osmotic pump. Results dsRNA/poly(I:C), but not other TLR ligands, highly stimulated ET-1 protein and mRNA (EDN1), as well as intercellular adhesion molecule-1 (ICAM-1) and IFN-regulated MX2, by endothelial cells and dermal fibroblasts. Poly(I:C) induced EDN1, ECE1, and ICAM-1 mRNA expression in poly(I:C) treated skin. Poly(I:C)-induced EDN1, ECE1 and MX2 was not blocked in mice with the type I IFN receptor deleted. However, poly(I:C)-induced EDN1 and ECE1, but not poly(I:C)-induced ICAM-1 expression was blocked in mice with the TLR3 signalling protein TRIF/TICAM-1 deleted. Conclusion Together these data show that the dsRNA can regulate genes associated with vascular activation, as seen in SSc, that type I IFNs do not mediate these effects, and that EDN1 and ECE1 but not ICAM-1 activation is mediated by TLR3.