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Inflammatory interaction between LIGHT and proteinase-activated receptor-2 in endothelial cells: potential role in atherogenesis.
Circ Res. 2009 Jan 02; 104(1):60-8.CircR

Abstract

The interaction between inflammatory cytokines and endothelial cells is a critical step in atherogenesis leading to endothelial dysfunction and inflammation. We have previously reported that the tumor necrosis factor superfamily member LIGHT could be involved in atherogenesis through its ability to promote vascular inflammation. In the present study we identified proteinase-activated receptor (PAR)-2 as an inflammatory mediator that was markedly enhanced by LIGHT in endothelial cells. We also found that LIGHT acted synergistically with PAR-2 activation to promote enhanced release of the proatherogenic chemokines interleukin-8 and monocyte chemoattractant protein-1, underscoring that the interaction between LIGHT and PAR-2 is biologically active, promoting potent inflammatory effects. We showed that the LIGHT-mediated upregulation of PAR-2 in endothelial cells is mediated through the HVEM receptor, involving Jun N-terminal kinase signaling pathways. A LIGHT-mediated upregulation of PAR-2 mRNA levels was also found in human monocytes when these cells were preactivated by tumor necrosis factor alpha. We have previously demonstrated increased plasma levels of LIGHT in unstable angina patients, and here we show a similar pattern for PAR-2 expression in peripheral blood monocytes. We also found that LIGHT, LIGHT receptors, and PAR-2 showed enhanced expression, and, to some degree, colocalization in endothelial cells and macrophages, in the atherosclerotic plaques of ApoE(-/-) mice, suggesting that the inflammatory interaction between LIGHT and PAR-2 also may be operating in vivo within an atherosclerotic lesion. Our findings suggest that LIGHT/PAR-2-driven inflammation could be a pathogenic loop in atherogenesis potentially representing a target for therapy in this disorder.

Authors+Show Affiliations

Research institute for Internal Medicine, Rikshospitalet University Hospital, University of Oslo, Norway. wiggo.sandberg@rr-research.noNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19023130

Citation

Sandberg, Wiggo J., et al. "Inflammatory Interaction Between LIGHT and Proteinase-activated Receptor-2 in Endothelial Cells: Potential Role in Atherogenesis." Circulation Research, vol. 104, no. 1, 2009, pp. 60-8.
Sandberg WJ, Halvorsen B, Yndestad A, et al. Inflammatory interaction between LIGHT and proteinase-activated receptor-2 in endothelial cells: potential role in atherogenesis. Circ Res. 2009;104(1):60-8.
Sandberg, W. J., Halvorsen, B., Yndestad, A., Smith, C., Otterdal, K., Brosstad, F. R., Frøland, S. S., Olofsson, P. S., Damås, J. K., Gullestad, L., Hansson, G. K., Oie, E., & Aukrust, P. (2009). Inflammatory interaction between LIGHT and proteinase-activated receptor-2 in endothelial cells: potential role in atherogenesis. Circulation Research, 104(1), 60-8. https://doi.org/10.1161/CIRCRESAHA.108.188078
Sandberg WJ, et al. Inflammatory Interaction Between LIGHT and Proteinase-activated Receptor-2 in Endothelial Cells: Potential Role in Atherogenesis. Circ Res. 2009 Jan 2;104(1):60-8. PubMed PMID: 19023130.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inflammatory interaction between LIGHT and proteinase-activated receptor-2 in endothelial cells: potential role in atherogenesis. AU - Sandberg,Wiggo J, AU - Halvorsen,Bente, AU - Yndestad,Arne, AU - Smith,Camilla, AU - Otterdal,Kari, AU - Brosstad,Frank R, AU - Frøland,Stig S, AU - Olofsson,Peder S, AU - Damås,Jan K, AU - Gullestad,Lars, AU - Hansson,Göran K, AU - Oie,Erik, AU - Aukrust,Pål, Y1 - 2008/11/20/ PY - 2008/11/22/pubmed PY - 2009/2/12/medline PY - 2008/11/22/entrez SP - 60 EP - 8 JF - Circulation research JO - Circ Res VL - 104 IS - 1 N2 - The interaction between inflammatory cytokines and endothelial cells is a critical step in atherogenesis leading to endothelial dysfunction and inflammation. We have previously reported that the tumor necrosis factor superfamily member LIGHT could be involved in atherogenesis through its ability to promote vascular inflammation. In the present study we identified proteinase-activated receptor (PAR)-2 as an inflammatory mediator that was markedly enhanced by LIGHT in endothelial cells. We also found that LIGHT acted synergistically with PAR-2 activation to promote enhanced release of the proatherogenic chemokines interleukin-8 and monocyte chemoattractant protein-1, underscoring that the interaction between LIGHT and PAR-2 is biologically active, promoting potent inflammatory effects. We showed that the LIGHT-mediated upregulation of PAR-2 in endothelial cells is mediated through the HVEM receptor, involving Jun N-terminal kinase signaling pathways. A LIGHT-mediated upregulation of PAR-2 mRNA levels was also found in human monocytes when these cells were preactivated by tumor necrosis factor alpha. We have previously demonstrated increased plasma levels of LIGHT in unstable angina patients, and here we show a similar pattern for PAR-2 expression in peripheral blood monocytes. We also found that LIGHT, LIGHT receptors, and PAR-2 showed enhanced expression, and, to some degree, colocalization in endothelial cells and macrophages, in the atherosclerotic plaques of ApoE(-/-) mice, suggesting that the inflammatory interaction between LIGHT and PAR-2 also may be operating in vivo within an atherosclerotic lesion. Our findings suggest that LIGHT/PAR-2-driven inflammation could be a pathogenic loop in atherogenesis potentially representing a target for therapy in this disorder. SN - 1524-4571 UR - https://www.unboundmedicine.com/medline/citation/19023130/Inflammatory_interaction_between_LIGHT_and_proteinase_activated_receptor_2_in_endothelial_cells:_potential_role_in_atherogenesis_ L2 - https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.108.188078?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -