iNOS (NOS2) at a glance

Abstract

Nitric oxide (NO) is an effector of the innate immune system. The innate immune system is a set of rapid host responses to pathogens. Cells of the innate immune system – macrophages, neutrophils and natural killer cells – use pattern recognition receptors to recognize molecular patterns associated with pathogens (Medzhitov, 2001). Activated macrophages then inhibit pathogen replication by releasing a variety of effector molecules, including NO. Extracellular signals trigger innate immunity Resting immune cells lack the inducible NO synthase (iNOS or NOS2), the enzyme that synthesizes NO. However, a variety of extracellular stimuli can activate distinct signaling pathways that converge to initiate expression of NOS2. Cell wall components of bacteria and fungi can trigger the innate immune signaling cascade, leading to expression of NOS2. For example, lipopolysaccharide (LPS), a component of the wall of Gram-negative bacteria, can bind to LPS-binding protein (LBP), which delivers LPS to CD14, a high-affinity LPS receptor. Toll-like receptor 4 (TLR4) in conjunction with the small extracellular protein MD-2 interacts with the CD14-LPS complex, and then activates an intracellular signaling cascade via adaptors that include IRAK and MyD88, which in turn activate downstream molecules including TRAF6. The innate immune pathway then activates signaling pathways including the mitogen-activated protein kinase (MAPK) pathway and the nuclear factor κB (NF-κB) pathway. These pathways converge to activate NOS2 transcription. Cytokines released from infected host cells can also activate NO production, including tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Interferon γ (IFN-γ) produced by activated immune cells can activate NOS2 expression, and can synergistically activate NOS