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

Figure 9

VPA induces apoptosis and inhibits IL-4 production in Tγδ lymphocytes. The proliferation of Tγδ lymphocytes arising from PBMC cultures, which are stimulated with IL-2 and zoledronic acid, is related to the promotion by the latter of the inhibition of the mevalonate pathway in monocytes, which upregulates pyrophosphate isopentenyl. This molecule is probably identified by the TCR of lymphocytes, but this has not been demonstrated. Furthermore, IL-2 sends proliferation and survival signals to these cells. However, VPA inhibits those mechanisms by promoting an increase in the intracellular molecules IL-4δ₁₃ and IL-4Rα, which have a direct effect on the induction of apoptosis and on the inhibition of IL-4 by blocking the AP1 signaling pathway. One additional VPA-related effect is the increase in H3 acetylation at the IL-4 locus, as well as a reduction in both CD95 and NKG2D. 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. Figure based on [111].