The transcription factor NF-kappaB has served as a standard for inducible transcription factors for more than 20 years. The numerous stimuli that activate NF-kappaB, and the large number of genes regulated by NF-kappaB, ensure that this transcription factor is still the subject of intense research. Here, we attempt to synthesize some of the basic principles that have emerged from studies of NF-kappaB, and we aim to generate a more unified view of NF-kappaB regulation.

The transcription factor NF-B has been the focus of intense investigation for nearly two decades. Over this period, considerable progress has been made in determining the function and regulation of NF-B, although there are nuances in this important signaling pathway that still remain to be understood. The challenge now is to reconcile the regulatory complexity in this pathway with the complexity of responses in which NF-B family members play important roles. In this review, we provide an overview of established NF-B signaling pathways with focus on the current state of research into the mechanisms that regulate IKK activation and NF-B transcriptional activity.

The ability to sense and adjust to the environment is crucial to life. For multicellular organisms, the ability to respond to external changes is essential not only for survival but also for normal development and physiology. Although signaling events can directly modify cellular function, typically signaling acts to alter transcriptional responses to generate both transient and sustained changes. Rapid, but transient, changes in gene expression are mediated by inducible transcription factors such as NF-κB. For the past 25 years, NF-κB has served as a paradigm for inducible transcription factors and has provided numerous insights into how signaling events influence gene expression and physiology. Since its discovery as a regulator of expression of the κ light chain gene in B cells, research on NF-κB continues to yield new insights into fundamental cellular processes. Advances in understanding the mechanisms that regulate NF-κB have been accompanied by progress in elucidating the biological significance of this transcription factor in various physiological processes. NF-κB likely plays the most prominent role in the development and function of the immune system and, not surprisingly, when dysregulated, contributes to the pathophysiology of inflammatory disease. As our appreciation of the fundamental role of inflammation in disease pathogenesis has increased, so too has the importance of NF-κB as a key regulatory molecule gained progressively greater significance. However, despite the tremendous progress that has been made in understanding the regulation of NF-κB, there is much that remains to be understood. In this review, we highlight both the progress that has been made and the fundamental questions that remain unanswered after 25 years of study.

No abstract

SUMMARY Metabolic disorders including obesity, type 2 diabetes and atherosclerosis have been viewed historically as lipid storage disorders brought about by overnutrition. It is now widely appreciated that chronic low-grade inflammation plays a key role in the initiation, propagation and development of metabolic diseases. Consistent with its central role in coordinating inflammatory responses, numerous recent studies have implicated the transcription factor NF-κB in the development of such diseases, thereby further establishing inflammation as a critical factor in their etiology and offering hope for the development of new therapeutic approaches for their treatment.

Research on the biological function of nuclear factor-kappaB (NF-kappaB), a key mediator of inducible transcription in the immune system, has traditionally focused on its role in the initiation of innate and adaptive immune responses. These studies have largely concentrated on the mechanisms of signalling that lead to NF-kappaB activation and on the positive role of NF-kappaB in both physiological immunity and pathological inflammation. More recently, there has been growing interest in the mechanisms that directly regulate the NF-kappaB transcriptional programmes. As a result, several new NF-kappaB regulatory components have been identified and some of the known components have been assigned new roles. In this Review, we discuss these new insights into the regulation of NF-kappaB.

No abstract

Mammalian Toll-like receptors (TLRs) play an important role in the innate recognition of pathogens by dendritic cells (DCs). Although TLRs are clearly involved in the detection of bacteria and viruses, relatively little is known about their function in the innate response to eukaryotic microorganisms. Here we identify a profilin-like molecule from the protozoan parasite Toxoplasma gondii that generates a potent interleukin-12 (IL-12) response in murine DCs that is dependent on myeloid differentiation factor 88. T. gondii profilin activates DCs through TLR11 and is the first chemically defined ligand for this TLR. Moreover, TLR11 is required in vivo for parasite-induced IL-12 production and optimal resistance to infection, thereby establishing a role for the receptor in host recognition of protozoan pathogens.