The NF-#cB transcription factor complex is sequestered in the cytoplasm by the inhibitory protein I#cB-a (MAD-3). Various cellular stimuli relieve this inhibition by mechanisms largely unknown, leading to NF-KB nuclear localization and transactivation of its target genes. It is demonstrated here with human T lymphocytes and monocytes that different stimuli, including tumor necrosis factor a and phorbol 12-myristate 13-acetate, cause rapid degradation ofIOcB-a, with concomitant activation of NF-cB, followed by a dramatic increase in IKB-a mRNA and protein synthesis. Transfection studies reveal that the IKB-a mRNA and the encoded protein are potently induced by NF-cB and by homodimers of p65 and of c-Rel. We propose a model in which NF-.cB and IKB-a mutually regulate each other in a cycle: saturating amounts of the inhibitory IKB-a protein are destroyed upon stimulation, allowing rapid activation of NF-KB. Subsequently, IcB-a mRNA and protein levels are qulickly induced by the activated NF-cB. This resurgence of IKB-a protein acts to restore an equilibrium in which NF-KB is again inhibited.NF-KB is a dimeric transcription factor that binds and regulates gene expression through decameric cis-acting KB DNA motifs (reviewed in refs. 1 and 2). Although a p50/p65 heterodimer has traditionally been referred to as NF-KB and remains the prototypical and most abundant form, it has been recognized recently that several distinct but closely related homo-and heterodimeric factors are responsible for KB site-dependent DNA binding activity and regulation. The various dimeric factors are composed of members of the family of Rel-related polypeptides. One subclass of this family, distinguished by its proteolytic processing from precursor forms and lack of recognized activation domains, includes p50 (NFKB1) (3-6) and pSOB (NFKB2, pS2) (7-10), whereas the second subclass contains recognized activation domains and includes p65 (RelA) (11-13), RelB (14,15),18) Activation of the NF-KB transcription factor and various related forms can be initiated by a variety of agents, including tumor necrosis factor a (TNF-a) and phorbol 12-myristate 13-acetate (PMA) (1, 2). Activation proceeds through a post-translational event in which preformed cytoplasmic NF-KB is released from a cytoplasmic inhibitory protein, (20)(21)(22)(23). IKB-a inhibits transactivation of the p50/p65 heterodimer, by binding to the p65 component, blocking the dimer's translocation to the nucleus (20,21,23). IKB-a also inhibits complexes containing c-Rel or RelB (24,25). IKB-a blocks binding in vitro of various NF-KB dimers to KB binding sites in DNA (11,12,15,22,26,27). Because the latter effect requires nuclear IKB-a, its relevance, in vivo, is unknown. Although lKB-a is generally a cytoplasmic protein (21, 23), it and its chicken homolog (pp4O) have also been detected in the nucleus (refs. 28-30 and K.B., G.F., and U.S., unpublished results). In addition to the wellcharacterized and cloned IKB-a and its chicken and rat homologs (24, 31), another biochemically d...

NF-kappa B is usually activated by signal-induced, ubiquitin-mediated degradation of its inhibitor, I kappa B. This process is initiated by phosphorylation of I kappa B by the I kappa B kinase (IKK) complex, predominantly by the IKK beta catalytic subunit, and requires the regulatory subunit IKK gamma (NEMO). Another activation pathway, with no known physiological inducers, involves ubiquitin-mediated processing of the NF-kappa B2 inhibitory protein p100 and is dependent on phosphorylation of p100 by IKK alpha. We show here that B cell-activating factor (BAFF) activates this second pathway and that this requires the BAFF receptor (BAFF-R), the NF-kappa B-inducing kinase (NIK) and protein synthesis, but not NEMO. This NEMO-independent cascade is physiologically relevant for the survival and, hence, progression of maturing splenic B cells.

Bcl-3 is an I kappa B-related protein with ankyrin repeat motifs. Its gene is located at a site of recurrent translocations in a subset of B cell chronic lymphocytic leukemias. Bcl-3 associates tightly with p50B (NFKB2, p52) homodimers in cells, and together these proteins form a ternary complex with DNA at kappa B sites. Such an association functionally leads to a novel and potent form of transactivation through the kappa B motif: the tethering of Bcl-3 to DNA via the p50B homodimers allows Bcl-3 to transactivate directly, while p50B homodimers alone cannot. Transactivation mediated by Bcl-3 requires two cooperating domains located amino- and carboxy-terminal to the ankyrin domain. Bcl-3 is localized to the nucleus, and a Bcl-3-p50B complex is detected in certain lymphoid cells. Our data reveal a novel role for Bcl-3, distinct from that of the inhibitor I kappa B. The results have implications for tumorigenesis.

Background-Carotenoids are hypothesized to explain some of the protective effects of fruit and vegetable intake on risk of cardiovascular disease. The present study assessed the protective effects of the oxygenated carotenoid lutein against early atherosclerosis. Methods and Results-Epidemiology: Progression of intima-media thickness (IMT) of the common carotid arteries over 18 months was determined ultrasonographically and was related to plasma lutein among a randomly sampled cohort of utility employees age 40 to 60 years (nϭ480). Coculture: The impact of lutein on monocyte response to artery wall cell modification of LDL was assessed in vitro by quantification of monocyte migration in a coculture model of human intima. Mouse models: The impact of lutein supplementation on atherosclerotic lesion formation was assessed in vivo by assigning apoE-null mice to chow or chow plus lutein (0.2% by weight) and LDL receptor-null mice to Western diet or Western diet plus lutein. IMT progression declined with increasing quintile of plasma lutein (P for trendϭ0.007, age-adjusted; Pϭ0.0007, multivariate). Covariate-adjusted IMT progression (meanϮSEM) was 0.021Ϯ0.005 mm in the lowest quintile of plasma lutein, whereas progression was blocked in the highest quintile (0.004Ϯ0.005 mm; Pϭ0.01).In the coculture, pretreatment of cells with lutein inhibited LDL-induced migration in a dose-dependent manner (PϽ0.05). Finally, in the mouse models, lutein supplementation reduced lesion size 44% in apoE-null mice (Pϭ0.009) and 43% in LDL receptor-null mice (Pϭ0.02). Conclusions-These epidemiological, in vitro, and mouse model findings support the hypothesis that increased dietary intake of lutein is protective against the development of early atherosclerosis.

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Much more teen smoking cessation research is needed, but teen smoking cessation programming is effective, and the present study provides a framework to move forward.

Previous studies have implicated acculturation to the US as a risk factor for unhealthy behaviors among Hispanic and Asian-American adolescents, including substance use, violence, and unsafe sex. This study examined the association between acculturation and obesity-related behaviors-physical activity and fast-food consumption-among 619 Asian-American and 1385 Hispanic adolescents in Southern California. Respondents completed surveys in 6th and 7th grade. The 6th grade survey assessed acculturation with the AHIMSA acculturation scale and a measure of English language usage. The 7th grade survey assessed frequency of moderate-to-intense physical activity and frequency of eating fast-food. Multiple regression analyses included acculturation and demographic covariates as predictors of physical activity and fast-food consumption. Acculturation to the US, assessed in 6th grade, was significantly associated with a lower frequency of physical activity participation and a higher frequency of fast-food consumption in 7th grade. The significant associations persisted after controlling for covariates and were consistent across gender and ethnic groups. Results suggest that acculturation to the US is a risk factor for obesity-related behaviors among Asian-American and Hispanic adolescents. Health promotion programs are needed to encourage physical activity and healthy diets among adolescents in acculturating families.

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