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Identifier

000369299

Title

Επίδραση των νευροπεπτιδίων της οικογένειας του εκλυτικού παράγοντα της κορτικοτροπίνης (CRF)και της λιποκίνης αδιπονεκτίνη στην τοπική ρύθμιση της φλεγμονής

Alternative Title

Effect of the CRF family of peptides and of the adipokine adiponectin in the regulation of inflammation

Author

Ζαχαριουδάκη, Βασιλική.

Thesis advisor

Τσατσάνης, Χρήστος

Reviewer

Μαργιωρής, Ανδρέας
Γραβάνης, Αχιλλέας
Βενυχάκη, Μαρία
Ηλιόπουλος, Αριστείδης
Καρδάσης, Δημήτριος
Μπούμπας, Δημήτριος

Abstract

CRF and Urocortins are major regulators of the inflammatory process. When released at the site of inflammation from nerve terminals, epithelial and immune cells, they affect directly the immune system, at the level of macrophage activation, exerting either pro-inflammatory or anti-inflammatory effects, depended on several factors among which the presence of other immuno-modulatory molecules at the site of inflammation is included. Adiponectin serves as such a molecule and its principal effect on macrophages is accepted to be anti-inflammatory. In this study, we investigate the effect of CRF and Urocortins on the regulation of adiponectin receptors AdipoR1 and AdipoR2 and on the adiponectin- and LPS-induced production of pro-inflammatory cytokines in macrophages. We found that CRF and Urocortins did not affect the effect of adiponectin on macrophages. The anti-inflammatory effects of adiponectin are believed to be exerted via macrophages, through suppression of the production of pro-inflammatory cytokines in response to LPS, via yet unknown signaling pathways. In this study we investigate the molecular mechanisms of macrophage tolerance driven by adiponectin. We show that macrophage tolerance did not occur at the adiponectin receptor level. At the early phase of the inflammatory response adiponectin regulates its magnitude via the activation of PI3K/Akt pathway, which in turn suppresses the activation of LPS-induced signaling pathways, such as the MEK/ERK pathway. In the long term, adiponectin induces the expression of IRAK-M protein, which acts as a dominant negative molecule on the activation of TLR-induced pathways, thus providing a late-stage potential mechanism through which adiponectin promotes tolerance of macrophages to LPS. Homologous deletion of IRAK-M abolished the tolerogenic properties of gAd, in terms of LPS-induced pro-inflammatory cytokine production from macrophages. Analysis of IRAK-M expression in human peripheral blood cells confirmed that serum adiponectin was positively associated with IRAK-M levels and negatively associated with the responsiveness of the cells to LPS. Finally, we show that adiponectin-induced glucose uptake from macrophages is necessary for the induction of macrophage tolerance, thus implying that the “tolerogenic state” is an active, energy-consuming process.

Language

Greek

Subject

Adiponectin

Biochemistry

IRAK-M

Inflammation

Macrophages

Αδιπονεκτίνη

Μακροφάγα

Φλεγμονή

Issue date