Lactic acid in vaginal secretions originates from the activity of both the vaginal mucosa (Gorodeski et al., 2005) and the action of Lactobacillus sp. and possibly also by other bacterial species (Zhou et al., 2004). Glucose LGK-974 in vivo in the intermediate vaginal epithelial cell layer under the influence of estrogen

is metabolized under anaerobic conditions to pyruvic acid and then to lactic acid. The lactic acid diffuses out of the cells and accumulates in the extracellular fluid. Similarly, Lactobacillus sp. convert extracellular glucose into lactic acid by anaerobic glycolysis. The activation of polymorphonuclear leukocytes and monocytes/macrophages is an energy-dependent process and stimulates the induction of glycolysis. Thus, inflammation is also associated with localized lactic acid release (Haji-Michael et al., 1999). Similarly, lactic acid is produced and released into the extracellular environment by many malignant tumors due to both accelerated aerobic glycolysis (the Warburg effect) (Warburg, 1961) and by anaerobic hypoxia-driven

glycolysis (Elson et al., 2000). The consequence of lactic acid release on immune system activities has not received much research attention. In a series of elegant experiments, Shime et al. (2008) demonstrated that a human lung adenocarcinoma cell line (CADO-LC10 cells) secreted lactic acid into the culture medium. While the lactic acid released by itself INK-128 had no effect on cytokine induction, in the concomitant presence of a Toll-like receptor (TLR) ligand, lactic acid stimulated the production of interleukin-23 (IL-23) by monocytes/macrophages. Conversely, there was no effect of lactic acid on

TLR-stimulated IL-12 transcription. IL-12 and IL-23 are heterodimeric cytokines that share a p40 subunit. In IL-12, p40 combines with a p35 subunit; in IL-23, p40 combines with p19 (Langrish et al., 2004). Thus, lactic acid enhanced p40 and p19 transcription drastically. The stimulation of IL-23 production required the presence Obatoclax Mesylate (GX15-070) of a lactate ion in its transportable form; the neutralized lactate anion or the presence of an equivalent proton concentration from a different acid did not enhance IL-23 release (Shime et al., 2008). IL-23 and IL-12 have unique effects on T helper lymphocyte subsets. IL-12 induces T cell differentiation into the Th1 CD4+ T cell subset. The release of interferon-γ (IFN-γ) by Th1 cells and natural killer cells activates macrophages to destroy intracellular microbial pathogens (Goriely et al., 2008). IFN-γ also acts on B lymphocytes to inhibit the synthesis of immunoglobulin G1 antibodies (Manetti et al., 1993). In contrast, IL-23 promotes the development of the newly recognized Th17 CD4+ T cell subset (Bettelli et al., 2007).