E-Locus - Institutional Repository of the University of Crete - Ο παράγοντας αναστολής της μετανάστευσης των μακροφάγων, MIF, ως ανταγωνιστής του μονοπατιού της αντιγονοπαρουσίασης στην επέκταση της μυελογενούς λευχαιμίας

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Identifier

000443040

Title

Ο παράγοντας αναστολής της μετανάστευσης των μακροφάγων, MIF, ως ανταγωνιστής του μονοπατιού της αντιγονοπαρουσίασης στην επέκταση της μυελογενούς λευχαιμίας

Alternative Title

Macrophage migration inhibitory factor MIF as an antagonist of the antigen presentation pathway in myelogenous leukemia expansion

Author

Βιτσιώτη, Αγνή Φ.

Thesis advisor

Αθανασάκη, Ειρήνη

Abstract

Surface MHC II antigen expression fires-up the antigen presentation process through the endocytic pathway and the consequent development of immune response. The absence of surface MHC II antigens is used by a variety of cancers, including leukemias, to escape immune surveillance. The invariant chain, Ii or CD74 is a key protein for the endocytic pathway and MHC II molecules, which apart from its role as a chaperone for MHC II molecules, is known to be a cognate receptor for macrophage migration inhibitory factor, MIF. Though, the triggering of a MIF signal transduction, which can promote cancer, requires a CD74 co-receptor, such as, CXCR4. In the present study, K562 and HL-60 leukemic cell lines were used, to determine by immunofluorescence and flow cytometry analysis, the effect of MIF and its receptors, CD74 and CXCR4 on the antigen presentation process, demonstrating a different behavior of CD74 in the two cell lines and consequently a differential antigen presentation potential. The absence of MHC II molecule expression from K562 cells has been correlated with the deficiency of the transcription factor CIITA. Using the stable trasfectants K562-CIITA-K9, the profile of the molecules of interest was determined, and it was shown that CIITA positively affected the intracellular levels of CD74 and CXCR4. The interchange of membrane and intracellular expression levels of the proteins of interest, posed the question of whether the enzymatic catabolism of MIF, CD74 kai CXCR4 could control pathogenesis of leukemic cells. Focusing on the catabolic action of cathepsins, which has been shown to relate with cancer cell propagation, the aspartyl-protease inhibitor, pepstatin-Α, was used to evaluate the phenotypic reversion of K562 and HL-60 cells. The results showed that pepstatin-A increased CD74 and MHC II intracellular levels in K562 cells, providing K562 a potential for effective antigen presentation processes, while highlighting pepstatin-A as a novel anti-cancer agent.

Language

Greek

Subject

CD74

CIITA

Cathepsin-D

Endocytic pathway

MHC II

Myelogenous Leykemia

Pepstatin-A

Ενδοκυτταρικό μονοπάτι

Καθεψίνη-D