Figure 6.

Proposed model of the effects of nigericin on bacterial killing in macrophages deficient of ASC. (1) Caspase-1 is modulated by nigericin via interactions with cathepsin B. Caspase-1 promotes cleavage of the pro-inflammatory cytokine pro-IL-18 (2) to active IL-18, which has been shown to induce upregulation of Cd40lg (3). CD40 is thought to play a key role in inflammatory diseases as hyperactivation of CD40 leads to increased production of pro-inflammatory cytokine, including IL-12 (4). Both IL-12 and IL-18 promote production of IFNγ (5). This cytokine plays a vital role in induction of the MHC class II complex (6), which is critical in macrophage defense against viral, protozoal, and some bacterial infections. IFNγ is an upstream activator of both MAPK and Ciita (7), also known as NLRA. The Ciita/STAT1 pathway is important for MHCII activation and antigen presentation following phagocytosis of bacteria in macrophages, while IFNγ and P38 promote phagocyte and bacterial killing pathways via oxidative burst by increased ROS production (8). Key mediators that were identified by gene array as increased by nigericin are highlighted in pink.