Objective: Microvascular endothelium is one of the main targets of the inflammatory response. On specific activation, endothelial cells recruit Th1-lymphocytes at the inflammatory site. We investigated the intracellular signaling mediating tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma inflammatory response in human microvascular endothelial cells (HMEC-1) and the interfering effects of the peroxisome-proliferator-activated-receptor (PPARgamma) agonist, rosiglitazone (RGZ). Methods and results: TNFalpha and IFNgamma, mainly when combined, stimulate IFNgamma-inducible protein of 10 kDa (IP10) and fractalkine production evaluated by ELISA and TaqMan analyses. This effect is not only mediated by activation of the NFkB and Stat1 classic pathways, but also involves a rapid increase in phosphorylation and activation of extracellular signal-regulated kinases (ERK1/2) as measured by Western blot. RGZ interferes with TNFalpha and IFNgamma stimulation of IP10, fractalkine, and adhesion molecule through a novel rapid mechanism which involves the blocking of ERK activation. Conclusions: Our findings shed new light on the mechanisms underlying the inflammatory response of microvascular endothelium and on the possible therapeutic use of RGZ in vasculopathies involving Th1-responses.

A new mechanism involving ERK contributes to rosiglitazone inhibition of tumor necrosis factor-alpha and interferongamma inflammatory effects inhuman endothelial cells

Varano G;
2008

Abstract

Objective: Microvascular endothelium is one of the main targets of the inflammatory response. On specific activation, endothelial cells recruit Th1-lymphocytes at the inflammatory site. We investigated the intracellular signaling mediating tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma inflammatory response in human microvascular endothelial cells (HMEC-1) and the interfering effects of the peroxisome-proliferator-activated-receptor (PPARgamma) agonist, rosiglitazone (RGZ). Methods and results: TNFalpha and IFNgamma, mainly when combined, stimulate IFNgamma-inducible protein of 10 kDa (IP10) and fractalkine production evaluated by ELISA and TaqMan analyses. This effect is not only mediated by activation of the NFkB and Stat1 classic pathways, but also involves a rapid increase in phosphorylation and activation of extracellular signal-regulated kinases (ERK1/2) as measured by Western blot. RGZ interferes with TNFalpha and IFNgamma stimulation of IP10, fractalkine, and adhesion molecule through a novel rapid mechanism which involves the blocking of ERK activation. Conclusions: Our findings shed new light on the mechanisms underlying the inflammatory response of microvascular endothelium and on the possible therapeutic use of RGZ in vasculopathies involving Th1-responses.
2008
Lombardi, A; Cantini, G; Piscitelli, E; Gelmini, S; Francalanci, M; Mello, T; Ceni, E; Varano, G; Forti, G; Rotondi, M; Galli, A; Serio, M; and Luconi...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2434613
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