The nuclear factor-kappaB (NF-kappaB)/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-kappaB 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-kappaB regulation and its role in the immune system and inflammatory diseases. We also discuss the role of NF-kappaB proteins as potential therapeutic targets in clinical applications.

Phosphorylation of inhibitor of kappa B (IkappaB) proteins is an important step in the activation of the transcription nuclear factor kappa B (NF-kappaB) and requires two IkappaB kinases, IKK1 (IKKalpha) and IKK2 (IKKbeta). Mice that are devoid of the IKK2 gene had extensive liver damage from apoptosis and died as embryos, but these mice could be rescued by the inactivation of the gene encoding tumor necrosis factor receptor 1. Mouse embryonic fibroblast cells that were isolated from IKK2-/- embryos showed a marked reduction in tumor necrosis factor-alpha (TNF-alpha)- and interleukin-1alpha-induced NF-kappaB activity and an enhanced apoptosis in response to TNF-alpha. IKK1 associated with NF-kappaB essential modulator (IKKgamma/IKKAP1), another component of the IKK complex. These results show that IKK2 is essential for mouse development and cannot be substituted with IKK1.

IB kinases (IKKs) IKK1 and IKK2 are two putative IB␣ kinases involved in NF-B activation. To examine the in vivo functions of IKK1, we generated IKK1-deficient mice. The mutant mice are perinatally lethal and exhibit a wide range of developmental defects. Newborn mutant mice have shiny, taut, and sticky skin without whiskers. Histological analysis shows thicker epidermis, which is unable to differentiate. Limbs and tail are wrapped inside the skin and do not extend properly out of the body trunk. Skeleton staining reveals a cleft secondary palate, split sternebra 6, and deformed incisors. NF-B activation mediated by TNF␣ and IL-1 is diminished in IKK1-deficient mouse embryonic fibroblast (MEF) cells. The IKK complex in the absence of IKK1 is capable of phosphorylating IB␣ and IB␤ in vitro. Our results support a role for IKK1 in NF-B activation and uncover its involvement in skin and skeleton development. We conclude further that the two related kinases IKK1 and IKK2 have distinct functions and can not be substituted for each other's functions. NF-B transcription factors are dimers composed of various combinations of structurally related proteins p50 (NF-B1), p52 (NF-B2), p65 (RelA), c-Rel, and RelB (for review, see Verma et al. 1995;Baeuerle and Baichwal 1997 ). In resting cells, NF-B complexes are retained in the cytoplasm in association with inhibitory proteins IBs (IB␣, I␤, I⑀). Upon stimulation by TNF␣, IL-1␣, UV, and ␥-irradiation, or bacterial and viral infection, IBs are phosphorylated at specific sites that lead to their ubiqitination, degradation by the proteosome, and release of NF-B proteins for translocation to the nucleus where they regulate expression of target genes.NF-B proteins play a major role in many physiological and pathological processes. Analyses of mice deficient in different members of the NF-B and IB families have revealed essential roles for these transcription factors in lymphocyte development and immune responses (for review, see Attar et al. 1997), fetal liver development (Beg et al. 1995), and osteoclast maturation (Franzoso et al. 1997;Iotsova et al. 1997). Rel/NF-B genes may also play a role in vertebrate limb development (Bushdid et al. 1998;Kanegae et al. 1998). Additionally, several groups have shown the involvement of NF-B proteins in antiapoptotic processes (Beg and Baltimore 1996; Van Antwerp et al. 1996;Wang et al. 1996). Lack of p65 (RelA) results in hepatocyte apoptosis and embryonic lethality at embryonic day 15 (E15), which may reflect its antiapoptotic function in hepatocytes during development (Beg et al. 1995).A central step to NF-B activation is the induced phosphorylation of IBs (Verma et al. 1995). Recently, the long-sought kinases for signal-induced phosphorylation of IB have been identified by three independent groups (DiDonato et al. 1997;Mercurio 1997;Regnier et al. 1997;Woronicz et al. 1997;Zandi et al. 1997). Two highly homologous IB kinases (IKKs), IKK1 (IKK␣) and IKK2 (IKK␤), are present in a large 700-900 kD complex and can specifically phosphorylate IB...

No abstract

Recombinant adenoviral vectors have recently been used to transfer genes into a number of different cell types in vitro and in vivo. A recombinant adenoviral vector bearing the Escherichia coli beta-galactosidase (beta-gal) gene was used to quantitate the frequency of hepatocyte transduction in the mouse after direct viral infusion into the portal vein. When 10(10) adenoviral particles were infused, over 95% of the hepatocytes were transduced in vivo as determined by x-gal staining. The transduction protocol is relatively safe in that there is no detectable helper virus production in transduced animals and that very few extrahepatic cells are transduced by this method. There is also no evidence of significant liver pathology unless substantially greater quantities of virus are used. However, the transduced hepatocytes do not appear to persist in vivo because the percentage of hepatocytes expressing beta-gal declined over time. Four months after the procedure, 0.5-10% of the hepatocytes contain detectable beta-gal activity in vivo. The change in beta-gal-positive cells correlates with decreasing amounts of adenoviral DNA. Thus, current recombinant adenoviral vectors may have clinical applications in gene therapy for acute hepatic disorders.