TNF and ROS Crosstalk in Inflammation

TNF is a proinflammatory cytokine with important functions in mammalian immunity and cellular homeostasis. Deregulation of TNFR signaling is associated with inflammatory diseases. ROS at low concentrations have important functions in regulating pathways such as TNFR1 signaling, but high ROS concentrations ultimately lead to DNA damage and cell death. Signaling pathways culminating in NF-κB activation are influenced by ROS and lead to upregulation of antioxidant proteins, demonstrating that TNF and ROS influence each other in a positive feedback loop. Regulation of the redox state and signaling is further complicated by TNF-induced production NO• and the formation of RNS. A better understanding of the interplay between TNF and ROS/RNS could reveal new therapeutic targets for many inflammatory diseases. Tumor necrosis factor (TNF) is tremendously important for mammalian immunity and cellular homeostasis. The role of TNF as a master regulator in balancing cell survival, apoptosis and necroptosis has been extensively studied in various cell types and tissues. Although these findings have revealed much about the direct impact of TNF on the regulation of NF-κB and JNK, there is now rising interest in understanding the emerging function of TNF as a regulator of the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). In this review we summarize work aimed at defining the role of TNF in the control of ROS/RNS signaling that influences innate immune cells under both physiological and inflammatory conditions. Tumor necrosis factor (TNF) is tremendously important for mammalian immunity and cellular homeostasis. The role of TNF as a master regulator in balancing cell survival, apoptosis and necroptosis has been extensively studied in various cell types and tissues. Although these findings have revealed much about the direct impact of TNF on the regulation of NF-κB and JNK, there is now rising interest in understanding the emerging function of TNF as a regulator of the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). In this review we summarize work aimed at defining the role of TNF in the control of ROS/RNS signaling that influences innate immune cells under both physiological and inflammatory conditions. an innate immune response that occurs at a site of tissue damage caused by either physical injury or a chemical or biological agent. Classic signs include heat, redness, pain, swelling, and loss of tissue function. Chronic inflammation can be pathological. the collection of leukocytes and their products that provides immediate defense against pathogens. Relies on recognition of common molecular motifs by pattern recognition receptors. a multifunctional organelle that is found in most eukaryotic cells and generates ATP. Considered to be the ‘energy powerhouse’ of the cell. process by which specific proteins in a cell disrupt the outer mitochondrial membrane and trigger the release of mitochondrial proteins that promote mitochondria-dependent cell death. autophagic removal of mitochondria under conditions of nutrient starvation or mitochondrial stress. transcription factor responsible for the expression of key cell survival genes. Following activation of the IKK complex, the inhibitor IκB that holds NF-κB in an inactive state in the cytoplasm is degraded, freeing NF-κB to translocate to the nucleus and drive gene expression. Chemically reactive oxygen- or nitrogen-derived molecules produced by various cellular mechanisms, including mitochondrial respiration. At low concentrations, ROS/RNS play key roles as messengers during cell signaling and proliferation. However, stress-related increases in ROS/RNS may result in significant damage to cellular components such as DNA and RNA, and trigger cell death. a cytokine participating in a broad range of cellular processes and responses including survival, differentiation, inflammation, and various forms of cell death.