Production of nitric oxide (NO) by activated macrophages is central to the control of infections. The inducible form of nitric oxide synthase (iNOS) is responsible for NO production in macrophages. Regulation of iNOS takes place at the level of transcription, with factors such as cytokines and bacterial products playing a prominent role.Among the cytokines, IFNγ is a major inducer of iNOS. IFNγ induces the transcription of iNOS by activating interferon regulated factor-1 (IRF-1) as well as the JAK/STAT pathway. In addition to the transcriptional activation of iNOS, IFNγ also induces the transcription of TNF. The endogenously produced TNF activates NF-κB, which in turn triggers the transcription of iNOS. Thus TNF and IFNγ demonstrate transcriptional synergy toward the expression of iNOS. Several bacterial products trigger toll like receptor (TLR) signaling via ERK/MAPK and PI3K signaling cascades. The triggering of the latter pathways culminates in the activation of transcription factors such as NF-κB, CREB binding protein (CBP) and AP-1 complex, which in turn results in the transcription of the iNOS gene.
In addition to NO, the microbicidal and tumoricidal properties of macrophages are dependent on the production of reactive oxygen species (ROS). The respiratory burst, which is the production of ROS, is largely attributed to the activation of the nicotinamide adenine diphosphate oxidase (NADPH oxidase). The latter enzyme complex is part of the electron transport chain, whose major membrane-bound components are gp-91 phox and p22 phox. The cytosolic components of NADPH oxidase include p47 phox and p67 phox. Factors such as bacterial products, hormones and chemicals can activate NADPH oxidase by enhancing the membrane translocation of its cytosolic subunits. In addition, several factors such as TNF, IFNγ and PPARα can enhance the expression of NADPH oxidase subunits, which in turn could lead to the activation of the enzyme.
This pathway highlights the important molecular events that lead to NO and ROS production in macrophages.