Generation of myeloid-derived suppressor cells using prostaglandin E2

Myeloid-derived suppressor cells (MDSCs) are natural immunosuppressive cells and endogenous inhibitors of the immune system. We describe a simple and clinically-compatible method of generating large numbers of MDSCs, using the cultures of peripheral blood-isolated monocytes supplemented with prostaglandin E2 (PGE2). We observed that PGE2 induces endogenous COX2 expression in cultured monocytes, blocking their differentiation into CD1a+ DCs and inducing the expression of IDO1, IL-4Ralpha, NOS2 and IL-10, typical MDSC-associated suppressive factors. The establishment of a positive feedback loop between PGE2 and COX2, the key regulator of PGE2 synthesis is necessary and sufficient to promote the development of CD1a+ DCs to CD14+CD33+CD34+ monocytic MDSCs in GM-CSF/IL-4-supplemented monocyte cultures, for their stability, production of multiple immunosuppressive mediators and CTL-suppressive function. In addition to PGE2, also selective EP2- and EP4-agonists, but not EP3/1 agonists, induce the MDSCs development, suggesting that other activators of the EP2- and EP2-driven signaling pathway (adenylate cyclase/cAMP/PKA/CREB) may be used to promote the development of suppressive cells. Our observations provide for a simple method to generate large numbers of MDSCs for the immunotherapy of autoimmune diseases, chronic inflammatory disorders and transplant rejection

Coenzyme Q and aging in the fruit fly Drosophila melanogaster

Aging is the consequence of the gradual accumulation of molecular and cellular damage during life. Oxidative damage due to mitochondrial malfunction seems to be the main contributor to aging. Although, recently it has been propose that reverse electron transport participate in signalling more than in damage the cell by ROS production. Other molecules has been described to take part in the aging process, as they are NAD, antioxidants and several microRNAs, as well new pathways that regulate the progression of aging. In addition, gene regulation due to epigenetic modification seems to be the responsible of providing a protective or permissive environment to age faster or slower. In this chapter, we review these things using the fruit fly as a model organism