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Identifier

000388608

Title

Μελέτη της εμπλοκής της κυτοκίνης οστεοποντίνης στην έναρξη και ανάπτυξη της εντερικής φλεγμονής

Alternative Title

Study of the role of cytokine osteopontin in the initiation and development of intestinal inflammation

Author

Κουρεπίνη, Ευαγγελία

Thesis advisor

Τσατσάνης, Χ.

Reviewer

Πανουτσακοπούλου, Β.
Παπαδάκη, Ε.
Ηλιόπουλος, Α.
Καρδάσης, Δ.
Σουρβίνος, Γ.
Σιδηρόπουλος, Π.

Abstract

Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), are caused by excessive inflammatory responses against commensal flora and other antigens present in the intestinal lumen. Alternations in intestinal dendritic cells (DCs) contribute to IBD development on humans and mice with experimental colitis (EC). Mesenteric lymph node (MLN) DCs are crucial mediators of colitis induction and they are separated in two main subsets that differentially express the integrin αΕ (CD103): CD11chighCD103+ and CD11chighCD103- DCs. Although both DC subsets are identified in MLNs during acute colitis, which DC subset mediates colitis initiation remains unknown. A recent study suggested the pro-inflammatory role for the cytokine osteopontin (Opn) in chronic EC. In addition, Opn is highly expressed in intestinal immune and non-immune mucosal cells, and in the plasma of IBD patients, as well as in colon and plasma of mice with EC. Opn expressed by DCs during autoimmunity contributes to the cellular mechanisms that mediate autoimmune diseases. Overall, Opn plays a role in modulating DC phenotype, recruitment and function during several inflammatory conditions. However, whether the crucial DC subset for colitis expresses Opn and the possible significance of DC-expressed Opn is unknown. The initial scope of this thesis was aimed in the identification of the critical DC subset for acute colitis induction. We found that the MLN CD103- DCs exhibit proinflammatory role in acute colitis. We address that apart from other inflammatory cytokines, CD103- DCs expressed very high levels of Opn during colitis. We also 10 found that Opn expression by CD103- DCs is critical for their inflammatory properties. By different experimental approaches, this thesis addresses that Opn expression by CD103- DCs could be solely responsible for their pro-inflammatory function. Thus, here we demonstrate for the first time that particularly Opn expression by CD103- DCs is crucial for their pro-inflammatory cytokine secretion. Opn expression boosted the special capability of CD103- DCs to drive type 1 CD4 T-helper cell (Th1) and Th17 cell polarization that mediate colitis. Additionally this thesis proposes a novel targeted therapeutic approach for colitis. Particularly, we show that neutralization of alpha 9 integrin that is a ligand for Opn, and is expressed specifically on CD103- DCs surface during colitis, blocked the pro-inflammatory action of Opn.

Language

English

Subject

Alfa 9 integrin

Colitis

Dendritic cell

Osteopontin

¨Αλφα 9 ιντεγκρίνη

Δενδριτικό κύτταρο

Κολίτιδα

Οστεοποντίνη

Issue date