Regulation of NF-κB by TNF family cytokines

• TNF family cytokines activate both canonical and noncanonical NF-κB signaling pathways.
• TNF/TNFR1 signaling serves as a model of the canonical NF-κB pathway.
• CD40L/CD40 signaling serves as a model of the noncanonical NF-κB pathway.
• The molecular mechanisms linking ligation of TNFR1 or CD40 to activation of the canonical or noncanonical NF-κB signaling pathway remain unclear.

The NF-κB family of inducible transcription factors is activated in response to a variety of stimuli. Amongst the best-characterized inducers of NF-κB are members of the TNF family of cytokines. Research on NF-κB and TNF have been tightly intertwined for more than 25 years. Perhaps the most compelling examples of the interconnectedness of NF-κB and the TNF have come from analysis of knock-out mice that are unable to activate NF-κB. Such mice die embryonically, however, deletion of TNF or TNFR1 can rescue the lethality thereby illustrating the important role of NF-κB as the key regulator of transcriptional responses to TNF. The physiological connections between NF-κB and TNF cytokines are numerous and best explored in articles focusing on a single TNF family member. Instead, in this review, we explore general mechanisms of TNF cytokine signaling, with a focus on the upstream signaling events leading to activation of the so-called canonical and noncanonical NF-κB pathways by TNFR1 and CD40, respectively.