Glucose-6-phosphate dehydrogenase (G6PD) activity can modulate macrophage response to Leishmania major infection

Glucose-6-phosphate dehydrogenase (G6PDH) ultimately plays a critical role in macrophage functions used against infectious agents. The present study investigated whether changes in G6PDH activity could influence the resistance of infected macrophages against Leishmania major infection. Mouse peritoneal and J774 macrophages were infected, respectively, ex vivo and in vitro, with L. major and then exposed to an inhibitor (6-aminonicotinamide) or activator (LPS + melatonin) of G6PDH activity for 24 h. Cell viability [using MTT assay] was measured to assess any direct toxicity from the doses of inhibitor/activator used for the macrophage treatments. Nitric oxide (NO) produced by the cells and released into culture supernatants was measured (Griess method) and cell G6PDH activity was also determined. Moreover, the number of amastigotes form Leishmania in macrophages that developed over a 7-d period was evaluated. The results showed that an increase in G6PDH activity after treatment of both types of macrophages with a combination of LPS + melatonin caused significant increases in NO production and cell resistance against L. major amastigote formation/survival. However, exposure to 6-aminonicotinamide led to remarkable suppression of G6PDH activity and NO production, events that were associated with a deterioration in cell resistance against (and an increase in cell levels of) the parasites. The results suggested that activation or suppression of G6PDH activity could affect leishmanicidal function of both mouse peritoneal and J774 macrophages. Thus, regulation of macrophages via modulation of G6PDH activity appears to provide a novel window for those seeking to develop alternative therapies for the treatment of leishmaniasis.