Nicotinamide as an anti-inflammatory agent: an in vivo and in vitro study in a mouse model of septic shock. (100.7)

Abstract

Abstract Tumor necrosis factor alpha is an important mediator of inflammation. Inhibition of TNF production is beneficial in several inflammatory diseases, and numerous efforts have been devoted in the design of therapies aimed at blocking the production of this cytokine. In the present work, we have analysed the anti inflammatory properties of nicotinamide (NAm), in a mouse model of acute septic shock. NAm was found to protect mice from a lethal injection of LPS, even when administered 2 h post treatment. NAm was found to inhibit TNF secretion while leading to increased IL-10 production in vivo. These observations have been corroborated by in vitro studies, in which NAm was found to inhibit TNF secretion by all the cell types tested. Our observations indicate that NAm only marginally affect TNF mRNA production while inhibiting TNF synthesis, suggesting an effect at a post-transcriptional stage. NAm represents an inhibitor of several classes of NAD dependent enzymes. To confirm the role of a NAD dependent step in the regulation of TNF, we took advantage of a novel pharmacological agent known to inhibit NAD synthesis (FK866). Use of this compound has led us to demonstrate that optimal TNF synthesis requires adequate intracellular NAD concentration. Collectively these studies establish a functional link between metabolism and inflammation, and suggest an important role for NAD dependent enzymes in the regulation of TNF synthesis.