NF-kappaB family of transcription factors: central regulators of innate and adaptive immune functions

Abstract

Transcription factors of the Rel/NF-kappaB family are activated in response to signals that lead to cell growth, differentiation, and apoptosis, and these proteins are critical elements involved in the regulation of immune responses. The conservation of this family of transcription factors in many phyla and their association with antimicrobial responses indicate their central role in the regulation of innate immunity. This is illustrated by the association of homologues of NF-kappaB, and their regulatory proteins, with resistance to infection in insects and plants (M. S. Dushay, B. Asling, and D. Hultmark, Proc. Natl. Acad. Sci. USA 93:10343-10347, 1996; D. Hultmark, Trends Genet. 9:178-183, 1993; J. Ryals et al., Plant Cell 9:425-439, 1997). The aim of this review is to provide a background on the biology of NF-kappaB and to highlight areas of the innate and adaptive immune response in which these transcription factors have a key regulatory function and to review what is currently known about their roles in resistance to infection, the host-pathogen interaction, and development of human disease.

FIG. 1.

Members of the Rel/NF-κB and IκB families of proteins. The arrows indicate the endoproteolytic cleavage sites of p105 and p100 which give rise to p50 and p52, respectively. Black boxes indicate the PEST domains, shaded boxes on Bcl-3 indicate transactivation domains, and gray boxes on RelB indicate leucine zipper domains. Abbreviations: RHD, Rel homology domain; ANK, ankyrin repeat; SS, signal-induced phosphorylation sites.

FIG. 2.

In unstimulated cells, the Rel/NF-κB homo- and heterodimers associate with members of the family of inhibitor proteins called IκB and remain as an inactive pool in the cytoplasm. Upon stimulation by different agents like IL-1, TNF-α, CD40L, LPS, or UV light, IκB molecules are rapidly phosphorylated, ubiquitinated, and degraded, allowing the NF-κB dimers to translocate to the nucleus and regulate transcription through binding to κB sites.