Missing Pieces in the NF-κB Puzzle

stimulate the migration and maturation of lymphocytes. Furthermore, NF-␬B is central for the overall immune response through its ability to activate genes coding for and cyclin D1, that are critical for apoptotic processes (Karin and Lin, 2002). regulation is the I␬B kinase (IKK) complex. This review is focused on recent progress as well as unanswered intriguing and outstanding questions that are likely to engage researchers in the near future. questions regarding the regulation and function of NF-␬B and IKK. NF-␬B Signaling Pathways NF-␬B represents a group of structurally related and Introduction evolutionarily conserved proteins, with five members in The recognition of pathogens by innate or adaptive im-p100) (reviewed in Ghosh et al., 1998). The mechanisms lymphocytes. The signal generated by the liganded re-by which the p105 and p100 precursor proteins are pro-ceptor is communicated to changes in gene expression cessed are not fully understood and were suggested to leading to enhanced expression of effector molecules involve either posttranslational or cotranslational events such as cytokines and adhesion molecules (Ghosh et al., This process depends is that while p105 processing is constitutive, the pro-on activation of various inducible transcription factors, cessing of p100 is regulated (Xiao et al., 2001). NF-␬B/ among which the NF-␬B transcription factors play an Rel proteins can exist as homo-or heterodimers, and evolutionarily conserved and critical role in the triggering although most NF-␬B dimers are activators of transcrip-and coordination of both innate and adaptive immune tion, the p50/p50 and p52/p52 homodimers can repress responses. The wide variety of genes regulated by the transcription of their target genes (Zhong et al., I␬Bs and retained in the cytoplasm. The I␬Bs are also demonstrated recently that genes encoding evolution-members of a gene family that contains seven known arily conserved antimicrobial peptides, such as ␤ defen-the precursor Rel proteins p100 and p105 (Ghosh et al., Zhang and Ghosh, 2001). NF-␬B also plays a role in 1998). Interestingly, p100 may serve both as an I␬B and expression of genes encoding molecules important for as a specific heterodimeric partner for RelB, such that the adaptive immune response, such as MHC proteins, its processing results in the release of p50:RelB hetero-costimulatory molecules such as B7.1, and cytokines dimers (Solan et al., 2002). The I␬Bs are characterized such as IL-2, IL-12, and IFN-␤ (Kopp and Medzhitov, by the presence of multiple ankyrin repeats, which are 1999). Additionally, some of the chemokines and cyto-protein-protein interaction domains that …