ISSN 1470-3947 (print)
ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology

Published by BioScientifica
Endocrine Abstracts (2007) 14 P13 
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Rosiglitazone interferes with the inflammatory response induced in human endothelial cells by TNFalpha and IFNgamma through a new mechanism involving extracellular signal-regulated kinases (ERKs)

Adriana Lombardi1, Elisabetta Piscitelli1, Michela Francalanci1, Tommaso Mello1, Veronica Santarlasci2, Stefania Gelmini1, Giulia Cantini1, Andrea Galli1, Lorenzo Cosmi2, Francesco Annunziato2, Gianni Forti1, Mario Serio1 & Michaela Luconi1

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Microvascular endothelium is one of the main character and target involved in the inflammatory response. Upon specific activation, endothelial cells massively recruit Th1 IFNgamma secreting lymphocytes at the inflammatory site. In the present study, we investigate the intracellular signalling mediating TNFalpha (T) and IFNgamma (I) inflammatory response in a human endothelial cell line (HMEC-1) in vitro and the interfering effects of rosiglitazone (RGZ), a peroxisome proliferator-activated receptor (PPARgamma) agonist currently used in clinical treatment of diabetes mellitus. We show that T and I alone stimulate interferon gamma-inducible protein-10 (IP-10) secretion by HMEC-1, effect which is dramatically increased when the two cytokines are used in combination. IP-10 secretion in response to T, I and RGZ is accompanied by a re-modulation of surface expression of cell adhesion molecules (CAM), such as VCAM-1 and ICAM-1. Although these stimulatory effects of T and I are mediated by a similar rapid increase in phosphorylation/activation of ERK1/2, as demonstrated by the use of ERK inhibitors, confocal microscopy analysis suggests that the synergistic action of T and I is partly mediated by a different subcellular localization of the activated ERKs. Concomitant treatment with RGZ reverts both activation of ERKs and interferes with IP-10 secretion and CAM expression elicited by T and I through a novel rapid mechanism not involving transcriptional activity of PPARgamma, as further confirmed by the inability of BADGE, an inhibitor of such a transactivational action, to revert RGZ effects. Our findings shed new light on the molecular mechanisms underlying the inflammatory response in the endothelium and on the possible therapeutic use of RGZ in such a process.

This study has been supported by project TRESOR of Region of Tuscany

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