AMP Affects Intracellular Ca2+ Signaling, Migration, Cytokine Secretion and T Cell Priming Capacity of Dendritic Cells

The nucleotide adenosine-5′-monophosphate (AMP) can be released by various cell types and has been shown to elicit different cellular responses. In the extracellular space AMP is dephosphorylated to the nucleoside adenosine which can then bind to adenosine receptors. However, it has been shown that AMP can also activate A1 and A2a receptors directly. Here we show that AMP is a potent modulator of mouse and human dendritic cell (DC) function. AMP increased intracellular Ca2+ concentration in a time and dose dependent manner. Furthermore, AMP stimulated actin-polymerization in human DCs and induced migration of immature human and bone marrow derived mouse DCs, both via direct activation of A1 receptors. AMP strongly inhibited secretion of TNF-α and IL-12p70, while it enhanced production of IL-10 both via activation of A2a receptors. Consequently, DCs matured in the presence of AMP and co-cultivated with naive CD4+CD45RA+ T cells inhibited IFN-γ production whereas secretion of IL-5 and IL-13 was up-regulated. An enhancement of Th2-driven immune response could also be observed when OVA-pulsed murine DCs were pretreated with AMP prior to co-culture with OVA-transgenic naïve OTII T cells. An effect due to the enzymatic degradation of AMP to adenosine could be ruled out, as AMP still elicited migration and changes in cytokine secretion in bone-marrow derived DCs generated from CD73-deficient animals and in human DCs pretreated with the ecto-nucleotidase inhibitor 5′-(alpha,beta-methylene) diphosphate (APCP). Finally, the influence of contaminating adenosine could be excluded, as AMP admixed with adenosine desaminase (ADA) was still able to influence DC function. In summary our data show that AMP when present during maturation is a potent regulator of dendritic cell function and point out the role for AMP in the pathogenesis of inflammatory disorders

Rational drug design applied to myeloperoxidase inhibition

Rational drug design is a general approach using protein-structure technique in which the discovery of a ligand can be driven either by chance, screening, or rational theory. Myeloperoxidase (MPO) was rapidly identified as a therapeutical target because of its involvement in chronic inflammatory syndromes. In this context, the research of MPO inhibitors was intensified and development of new chemical entities was rationally driven by the research of ligands that enter into the MPO catalytic pocket. Actually, as soon as crystallography data of MPO have become available and its structure was virtually designed, the rational drug design has been applied to this peroxidase. Pharmaceutical industries and academic laboratories apply rational drug design on MPO by either optimizing known inhibitors or searching new molecules by high-throughput virtual screening. By these ways, they were able to find efficient MPO inhibitors and understand their interactions with the enzyme. During this quest of MPO inhibition, it appears that Glu268 is a crucial residue in order to optimize ligandtarget interaction. This amino acid should be carefully considered by medicinal chemist when they design inhibitors interfering with MPO activity.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Orbiviruses

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