NF-κB regulation in the immune system

  • An Erratum to this article was published on 01 December 2002

Abstract

The nuclear factor-κB (NF-κB)/REL family of transcription factors has a central role in coordinating the expression of a wide variety of genes that control immune responses. There has been intense scientific activity in the NF-κB field owing to the involvement of these factors in the activation and regulation of key molecules that are associated with diseases ranging from inflammation to cancer. In this review, we focus on our current understanding of NF-κB regulation and its role in the immune system and inflammatory diseases. We also discuss the role of NF-κB proteins as potential therapeutic targets in clinical applications.

Key Points

  • Nuclear factor-κB (NF-κB) has a seminal role in immunity. Aberrant NF-κB activity is associated with various inflammatory diseases.

  • NF-κB activation is controlled by its cellular localization through its association with inhibitor of NF-κB (IκB) proteins. This is achieved by a dynamic shuttling of latent NF-κB–IκBα complexes between the cytoplasm and nucleus.

  • Most of the pathways that result in NF-κB activation converge on activating the IκB kinase (IKK) complex. Subsequently, IKK phosphorylates IκB, resulting in the degradation of IκB and the release of NF-κB, which translocates to the nucleus to bind specific DNA sequences.

  • Additional signalling pathways are required for NF-κB transactivation by modification of its phosphorylation sites.

  • NF-κB pathways provide many targets for developing specific drugs to treat inflammatory diseases.

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Figure 1: Mammalian NF-κB- and IκB-family members.
Figure 2: NF-κB activation pathways.
Figure 3: A model of how NF-κB phosphorylation regulates its transactivation function.

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Acknowledgements

Q.L. is a Special Research Fellow of the Leukemia and Lymphoma Society. I.M.V. is an American Cancer Society Professor of Molecular Biology. He is supported by grants from the National Institutes of Health, the March of Dimes, the Lebensfeld Foundation, the Wayne and Gladys Valley Foundation and the H.N. and Frances C. Berger Foundation.

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Correspondence to Inder M. Verma.

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DATABASES

Entrez

Listeria monocytogenes

InterPro

ankyrin repeat

RHD

TIR

LocusLink

AKT

B7-H

BCL-3

BCL-10

CBP

CD14

CD28

CD80

CD86

CDC37

CKII

COX2

GM-CSF

GSK3β

HDAC1

HDAC2

HDAC3

HSP90

IFN-γ

IκBα

IκBβ

IκBɛ

IKK1

IKK2

IKK-i

IL-1

IL-1R

IL-2

IL-4

IL-6

IL-8

IL-18

IRAK

MAGUK

MALT1

MD-2

MEKK1

MEKK2

MEKK3

MYD88

NEMO

NF-κB1

NF-κB2

NIK

iNOS

p300

PI3K

PKA

PKCθ

PKCζ

RANKL

c-REL

RELA

RELB

RIP

STAT5a

TAB1

TAB2

TAK1

TBK1

TLR2

TLR4

TNF

TNFR1

TPL2

TRADD

TRAF2

TRAF6

β-TRCP

OMIM

IP

MS

rheumatoid arthritis

Glossary

INCONTINENTIA PIGMENTI

(IP). This disease is characterized by abnormalities in ectodermal tissues, including the skin, eyes and central nervous system, and dentition. It is inherited as an X-linked dominant trait and is usually fatal for male fetuses.

ANHIDROTIC ECTODERMAL DYSPLASIA WITH IMMUNODEFICIENCY

(EDA-ID). X-linked and autosomal forms of EDA syndromes are characterized by the poor development of ectoderm-derived structures, including hair, teeth and exocrine glands. The recent cloning of the genes that underlie these syndromes — ectodysplasin 1 (ED1) and the ectodysplasin A receptor (EDAR) — has shown the protein products to be a new TNF ligand–receptor pair. EDA-ID is regarded as an independent, primary immunodeficiency syndrome owing to unusually severe infections or immunological abnormalities in some EDA patients.

ISOTYPE SWITCHING

When B cells change their class of antibody (immunoglobulin) production from one isotype to another — for example, from IgM to IgG.

ELECTROPHORETIC MOBILITY-SHIFT ASSAY

A technique for detecting DNA–protein complex formation. It involves the incubation of nuclear extracts with a radiolabelled oligonucleotide probe, then separating the probe that has bound nuclear proteins from the free radiolabelled probe by gel electrophoresis, followed by autoradiography.

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