The transcription factor NF-kappaB 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-kappaB, 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-kappaB family members play important roles. In this review, we provide an overview of established NF-kappaB signaling pathways with focus on the current state of research into the mechanisms that regulate IKK activation and NF-kappaB transcriptional activity.

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Signaling to NF-kappaB.

The nuclear factor NF-κB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-κB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules In this article, we describe how genetic evidence in mice has revealed complex roles for the NF-κB in inflammation that suggest both pro- and anti-inflammatory roles for this pathway NF-κB has long been considered the “holy grail” as a target for new anti-inflammatory drugs; however, these recent studies suggest this pathway may prove a difficult target in the treatment of chronic disease In this article, we discuss the role of NF-κB in inflammation in light of these recent studies

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The Nuclear Factor NF-κB Pathway in Inflammation

Nuclear factor-kappaB (NF-kappaB) transcription factors and the signalling pathways that activate them are central coordinators of innate and adaptive immune responses. More recently, it has become clear that NF-kappaB signalling also has a critical role in cancer development and progression. NF-kappaB provides a mechanistic link between inflammation and cancer, and is a major factor controlling the ability of both pre-neoplastic and malignant cells to resist apoptosis-based tumour-surveillance mechanisms. NF-kappaB might also regulate tumour angiogenesis and invasiveness, and the signalling pathways that mediate its activation provide attractive targets for new chemopreventive and chemotherapeutic approaches.

Nuclear factor-kappaB in cancer development and progression.

There has been much effort recently to probe the long-recognized relationship between the pathological processes of infection, inflammation and cancer. For example, epidemiological studies have shown that approximately 15% of human deaths from cancer are associated with chronic viral or bacterial infections. This Review focuses on the molecular mechanisms that connect infection, inflammation and cancer, and it puts forward the hypothesis that activation of nuclear factor-kappaB (NF-kappaB) by the classical, IKK-beta (inhibitor-of-NF-kappaB kinase-beta)-dependent pathway is a crucial mediator of inflammation-induced tumour growth and progression, as well as an important modulator of tumour surveillance and rejection.

NF-kappaB: linking inflammation and immunity to cancer development and progression.

Nuclear factor (NF)-kappaB and inhibitor of NF-kappaB kinase (IKK) proteins regulate many physiological processes, including the innate- and adaptive-immune responses, cell death and inflammation. Disruption of NF-kappaB or IKK function contributes to many human diseases, including cancer. However, the NF-kappaB and IKK pathways do not exist in isolation and there are many mechanisms that integrate their activity with other cell-signalling networks. This crosstalk constitutes a decision-making process that determines the consequences of NF-kappaB and IKK activation and, ultimately, cell fate.

Integrating cell-signalling pathways with NF-kappaB and IKK function.

Nuclear factor-κB (NF-κB)/Rel transcription factors have been suspected since their discovery to play a pivotal role in chronic and acute inflammatory diseases. It now seems that aberrant regulation of NF-κB could also underlie autoimmune diseases and different types of cancer. Recently, NF-κB and the signalling pathways that regulate its activity have become a focal point for intense drug discovery and development efforts. Given the large number of major ailments in which aberrant regulation of NF-κB has been observed or is suspected, such efforts seem well justified. This review will discuss recent progress in the development of drugs that inhibit NF-κB activation, and consider their potential applications in inflammatory and autoimmune diseases, as well as cancer.

Q May Wang

Papers

The IKK NF-kappa B system: a treasure trove for drug development.