Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) show opposing roles in the immune system. The establishment of positive feedback loop between prostaglandin E2 (PGE2) and COX2, the key regulator of PGE2 synthesis, represents the determining factor in redirecting the development of CD1a+ DCs to CD14+CD33+CD34+ monocytic MDSCs. Exogenous PGE2 and COX2 activators (LPS, IL1b orIFNg), all induce monocyte expression of COX2, blocking their differentiation into CD1a+ DCs and induce endogenous PGE2, IDO1, IL4Ra, NOS2 and IL10, typical MDSCassociated suppressive factors. The central role of COX2/PGE2 feedback in the induction and persistence of MDSCs highlights the potential for its manipulation to enhance or suppress immune responses in cancer, autoimmunity or transplantation. The central role of COX2/PGE2 feedback in the induction and persistence of MDSCs highlights the potential for its manipulation to enhance or suppress immune responses in cancer, autoimmunity or transplantation.
COBISS.SI-ID: 3111793
Signals mediated by CXCL12 (SDF1) and its receptor CXCR4 are centrally involved in cancer progression, both directly by activating cancer cells and indirectly by inducing angiogenesis plus recruiting T regulatory and plasmacytoid dendritic immune cells. In ascites isolated from ovarian cancer patients, both CXCL12 and CXCR4 are controlled by the tumor-associated inflammatory mediator prostaglandin E2 (PGE2), which attracts myeloid-derived suppressor cells (MDSC) into the ascites microenvironment. In this setting, PGE2 was essential both for expression of functional CXCR4 in cancer-associated MDSCs and for production of its ligand CXCL12. Frequencies of CD11b+CD14+CD33+CXCR4+ MDSCs closely correlated with CXCL12 and PGE2 levels in patient ascites. Together, our findings elucidate a central role for PGE2 in MDSC accumulation triggered by the CXCL12CXCR4 pathway, providing a powerful rationale to target PGE2 signaling in ovarian cancer therapy.
COBISS.SI-ID: 3141745
In this article, we describe the design, synthesis and activity evaluation of glycomimetic DC-SIGN antagonists, that use a mannose residue to anchor to the protein carbohydrate recognition domain (CRD). The molecules were designed from the structure of the known pseudo-mannobioside antagonist 1, by including additional hydrophobic groups, which were expected to engage lipophilic areas of DC-SIGN CRD. The results demonstrate that the synthesized compounds potently inhibit DC-SIGN-mediated adhesion to mannan coated plates. Additionally, in silico docking studies were performed to rationalize the results and to suggest further optimization.
COBISS.SI-ID: 2895473