Exploring the Drug Repurposing Versatility of Valproic Acid as a Multifunctional Regulator of Innate and Adaptive Immune Cells

Figure 8

VPA affects IL-12-, IL-15-, and IL-18-mediated IFN-γ production in NK cells. NK cells produce IFN-γ through signaling pathways that are activated by the presence of IL-12, IL-15, and IL-18. In response to IL-12, STAT4 is activated and STAT5 is phosphorylated, while IL-15 activates both STAT5 and the MAPK pathway and IL-18 induces NF-κB and the MAPK pathway. An intermediate of this path is p38 (not shown), which stabilizes the IFN-γ mRNA. This promotes a synergistic effect for the production of this cytokine. On the other hand, STAT5 activation promotes the expression of T-bet, recognized as the master regulator for IFN-γ expression. VPA also interferes with the production of this cytokine by reducing STAT5 phosphorylation and T-bet expression. Green arrows indicate the processes, molecules, or mediators in the signaling pathway that are augmented and/or promoted by VPA. Red arrows indicate processes, molecules, or mediators in the signaling pathway that are inhibited by VPA.