The two NF-κB activation pathways and their role in innate and adaptive immunity

doi:10.1016/j.it.2004.03.008

Trends in Immunology

Volume 25, Issue 6, 1 June 2004, Pages 280-288

https://doi.org/10.1016/j.it.2004.03.008 Get rights and content

Abstract

NF-κB was first described as a B-cell-specific transcription factor that binds the κB site in the Ig κ light chain enhancer. Soon after, NF-κB activity was found to be inducible in all cell types and it is now known that members of the NF-κB/Rel family regulate many genes involved in immune and inflammatory responses. Until recently, only a single NF-κB signaling pathway was known, whereby NF-κB activity is stimulated by proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), as well as by pathogen-associated molecular patterns (PAMPs). However, two years ago, a second pathway leading to NF-κB activation was discovered. This pathway, now known as the alternative pathway, is activated by certain members of the TNF cytokine family but not by TNF-α itself. Recent results strongly suggest that the classical and alternative pathways to NF-κB activation have distinct regulatory functions, one that is mostly involved in innate immunity and the other in adaptive immunity.

Section snippets

The classical pathway and innate immunity

It is well established that the classical NF-κB pathway, based on IKKβ-dependent IκB degradation, is essential for innate immunity. Deficiencies in RelA and IKKβ result in a marked increase in susceptibility to infections, once the embryonic lethality associated with these deficiencies is prevented 10, 11.

The activation and nuclear translocation of classical NF-κB dimers (mostly p50–RelA) is associated with increased transcription of genes encoding chemokines, cytokines, adhesion molecules

The alternative pathway: lymphoid organ development and adaptive immunity

In the developing mouse embryo, expression of Rel/NF-κB-family members in the spleen is detected around E17.5 [31]. In the adult mouse, Nfkb1, Nfkb2, RelA, RelB and c-Rel mRNAs are expressed in distinct regions of the spleen with highest levels in the white pulp [31]. These findings suggest distinct roles for different family members in spleen, development, function and/or organization (Table 2). This hypothesis is supported by analysis of knockout mice with targeted disruptions of individual

The basis for biological specificity in IKK action

As discussed above, the major function of IKKα in the immune system is related to the development and organization of secondary lymphoid organs and B-cell maturation, whereas IKKβ is essential for activation of innate immune responses and for maintaining survival of immune cells. Although the IKKβ-dependent classical NF-κB pathway might also be involved in lymphoid organogenesis, this function appears to be distinct and not overlapping with that of IKKα. By contrast, IKKα seems to be fully

Concluding remarks

On the basis of evolutionary considerations, the original function of the IKK–NF-κB signaling module was the activation of innate immune responses. Indeed, IKK and NF-κB are conserved in the fruit fly, where they are also involved in activation of innate immune responses [62]. Thus, the function of IKKα in adaptive immunity and lymphoid organ development is probably a more recent adaptation. An important part of innate immunity is the recruitment of professional immune cells (macrophages,

Acknowledgements

Work in M.K.’s laboratory was supported by grants from the National Institutes of Health (AI43477, ES10337, ES06376, DK35108). G.B. was supported by a postdoctoral fellowship from the Human Frontier Science Program. M.K. is an American Cancer Society Research Professor.

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Trends in Immunology

The two NF-κB activation pathways and their role in innate and adaptive immunity

Abstract

Section snippets

The classical pathway and innate immunity

The alternative pathway: lymphoid organ development and adaptive immunity

The basis for biological specificity in IKK action

Concluding remarks

Acknowledgements

Cell

Immunity

Mol. Cell

Immunity

Curr. Opin. Immunol.

Immunity

Immunity

Immunity

Cell

Cell

Immunity

Mol. Cell

NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses

Annu. Rev. Immunol.

RelB, a new Rel family transcription activator that can interact with p50-NF-κB

Mol. Cell. Biol.

I-Rel: a novel rel-related protein that inhibits NF-κB transcriptional activity

Genes Dev.

p105 and p98 precursor proteins play an active role in NF-κB mediated signal transduction

Genes Dev.

Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway

Science

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EMBO Rep.

Targeted mutation of TNF receptor I rescues the RelA-deficient mouse and reveals a critical role for NF-κB in leukocyte recruitment

J. Immunol.

NF-κB is a central regulator of the intestinal epithelial cell innate immune response induced by infection with enteroinvasive bacteria

J. Immunol.

Pulmonary epithelial cells are a source of IL-8 in the response to Mycobacterium tuberculosis: essential role of IL-1 from infected monocytes in a NF-κB-dependent network

J. Immunol.

Toll-like receptors and innate immunity

Nat. Rev. Immunol.

Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression

J. Immunol.

A Toll-like receptor recognizes bacterial DNA

Nature

Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3

Nature

The NF-κB family member RelB is required for innate and adaptive immunity to Toxoplasma gondii

J. Immunol.

The Rel subunit of NF-κB-like transcription factors is a positive and negative regulator of macrophage gene expression: distinct roles for Rel in different macrophage populations

EMBO J.

Cutting edge: identification of c-Rel-dependent and -independent pathways of IL-12 production during infectious and inflammatory stimuli

J. Immunol.

The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4

Nature

Disruption of signaling by Yersinia effector YopJ, a ubiquitin-like protein protease

Science

NF-κB RelA-deficient lymphocytes: normal development of T cells and B cells, impaired production of IgA and IgG1 and reduced proliferative responses

J. Exp. Med.

Severe liver degeneration in mice lacking the IκB kinase 2 gene

Science