The NF-κB transcription factor is the master regulator of the inflammatory response and is essential for the homeostasis of the immune system. NF-κB regulates the transcription of genes that control inflammation, immune cell development, cell cycle, proliferation, and cell death. The fundamental role that NF-κB plays in key physiological processes makes it an important factor in determining health and disease. The importance of NF-κB in tissue homeostasis and immunity has frustrated therapeutic approaches aimed at inhibiting NF-κB activation. However, significant research efforts have revealed the crucial contribution of NF-κB phosphorylation to controlling NF-κB directed transactivation. Importantly, NF-κB phosphorylation controls transcription in a gene-specific manner, offering new opportunities to selectively target NF-κB for therapeutic benefit. This review will focus on the phosphorylation of the NF-κB subunits and the impact on NF-κB function.

Immune homeostasis is essential for the normal functioning of the immune system, and its breakdown leads to fatal inflammatory diseases. We report here the identification of a member of the tumor necrosis factor-alpha-induced protein-8 (TNFAIP8) family, designated TIPE2, that is required for maintaining immune homeostasis. TIPE2 is preferentially expressed in lymphoid tissues, and its deletion in mice leads to multiorgan inflammation, splenomegaly, and premature death. TIPE2-deficient animals are hypersensitive to septic shock, and TIPE2-deficient cells are hyper-responsive to Toll-like receptor (TLR) and T cell receptor (TCR) activation. Importantly, TIPE2 binds to caspase-8 and inhibits activating protein-1 and nuclear factor-kappaB activation while promoting Fas-induced apoptosis. Inhibiting caspase-8 significantly blocks the hyper-responsiveness of TIPE2-deficient cells. These results establish that TIPE2 is an essential negative regulator of TLR and TCR function, and its selective expression in the immune system prevents hyperresponsiveness and maintains immune homeostasis.

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Toll-like receptors (TLRs) trigger the production of inflammatory cytokines and shape adaptive and innate immunity to pathogens. We report the identification of B cell leukemia (Bcl)-3 as an essential negative regulator of TLR signaling. By blocking ubiquitination of p50, a member of the nuclear factor (NF)-kB family, Bcl-3 stabilizes a p50 complex that inhibits gene transcription. As a consequence, Bcl-3-deficient mice and cells were found to be hypersensitive to TLR activation and unable to control responses to lipopolysaccharides. Thus, p50 ubiquitination blockade by Bcl-3 limits the strength of TLR responses and maintains innate immune homeostasis. These findings indicate that the p50 ubiquitination pathway can be selectively targeted to control deleterious inflammatory diseases.

Reactive oxygen species (ROS) are frequently associated with cytotoxicity, often being described as damaging, harmful or toxic. It is generally assumed that, under pathological circumstances, ROS elicit wide-spread and random acts of oxidation. This passive attack of cellular components by ROS, in conditions where oxidative stress is the initiating stimulus for apoptosis, is assumed to simply trigger cell death as a result of cumulative oxidative damage. However, accumulating evidence now suggests that ROS may act as signalling molecules for the initiation and execution of the apoptotic death programme in many, if not all, current models of apoptotic cell death. Signalling by ROS would not appear to be random, as previously assumed, but targeted at specific metabolic and signal transduction cellular components. There is also evidence that the enzymatic generation of ROS may not simply be an unwanted by-product of the primary reaction catalysed, but that ROS may be used as signalling molecules to regulate cellular processes including apoptosis. This view of ROS as signalling molecules (as opposed to toxic metabolites) has been further bolstered by the findings that cellular antioxidants such as glutathione and thioredoxin not only serve to regulate ROS levels but also act as reversible redox modifiers of enzyme function. This review will attempt to delineate the involvement of ROS in apoptosis in light of these recent discoveries and provide evidence for a crucial role for ROS in the initiation and execution of the death process.