The survival of transitional and mature B cells requires both the B cell antigen receptor (BCR) and BLyS receptor 3 (BR3), which suggests that these receptors send signals that are nonredundant or that engage in crosstalk with each other. Here we show that BCR signaling induced production of the nonclassical transcription factor NF-κB pathway substrate p100, which is required for transmission of BR3 signals and thus B cell survival. The capacity for sustained p100 production emerged during transitional B cell differentiation, the stage at which BCR signals begin to mediate survival rather than negative selection. Our findings identify a molecular mechanism for the reliance of primary B cells on continuous BR3 and BCR signaling, as well as for the gradual resistance to negative selection that is acquired during B cell maturation.Primary B cells rely on signals from both the B cell antigen receptor (BCR) and B lymphocyte stimulator (BLyS1; also called BAFF2; A000383) receptor 3 (BR3; also called BAFFr; A000374) for survival. Most peripheral B cells die after BCR ablation regardless of BR3 sufficiency, which indicates a need for continuous 'tonic' signals through the BCR3. Conversely, the lack of either BLyS or BR3, both of which are members of the tumor necrosis factor (TNF) family, results in B cell deficiency despite normal BCR function4-6. The requirement for both BCR and BR3 becomes apparent during transitional B cell differentiation and affects survival at the transitional 2 (T2) and T3 differentiation stages, such that the BCR signaling thresholds for negative and positive selection are modulated by BLyS availability7, 8. The molecular mechanism that underlies this codependence on BCR and BR3 is poorly understood.Correspondence should be addressed to M.P.C. (cancro@mail.med.upenn.edu). Accession codes. UCSD-Nature Signaling Gateway (http://www.signaling-gateway.org): A000383, A000374, A002936, A002248, A000374 and A000305.Note: Supplementary information is available on the Nature Immunology website. AUTHOR CONTRIBUTIONS J.E.S., M.K., F.G.K., J.L.S., J.P.M., W.J.Q., R.J.B., L.S.T. and K.A.J. did research, analyzed data and generated key reagents; J.E.S., M.K., J.G.M., R.S. and M.P.C. designed research and analyzed data; and J.E.S., R.S., M.K. and M.P.C. wrote the paper.Published online at http://www.nature.com/natureimmunology/ Reprints and permissions information is available online at

The transcription factor NFB plays a critical role in normal and pathophysiological immune responses. Therefore, NFB and the signaling pathways that regulate its activation have become a major focus of drug development programs. Withania somnifera (WS) is a medicinal plant that is widely used in Palestine for the treatment of various inflammatory disorders. In this study we show that the leave extract of WS, as well as its major constituent withaferin A (WA), potently inhibits NFB activation by preventing the tumor necrosis factor-induced activation of IB kinase ␤ via a thioalkylation-sensitive redox mechanism, whereas other WS-derived steroidal lactones, such as withanolide A and 12-deoxywithastramonolide, are far less effective. To our knowledge, this is the first communication of IB kinase ␤ inhibition by a plant-derived inhibitor, coinciding with MEK1/ ERK-dependent Ser-181 hyperphosphorylation. This prevents IB phosphorylation and degradation, which subsequently blocks NFB translocation, NFB/DNA binding, and gene transcription. Taken together, our results indicate that pure WA or WA-enriched WS extracts can be considered as a novel class of NFB inhibitors, which hold promise as novel anti-inflammatory agents for treatment of various inflammatory disorders and/or cancer.

NF-κB proteins were identified in the search for mechanisms that regulate B-lymphocyte-specific transcription of immunoglobulin κ light chain genes. Twenty-five years later, though the function of the κB site in the enhancer remains enigmatic, NF-κB proteins have been shown to have important roles in B-cell development, maintenance, and function. In this review, we summarize the functions of NF-κB in B cells. An overview of B-cell biology that identifies stages in the life of B lymphocytes for the general reader is followed by three sections that examine the role of NF-κB family of proteins in B-cell development, mature B-cell survival and B-cell function. We endeavor throughout to suggest mechanisms and implications of the wide-ranging observations that have been made and conclude by highlighting the need to understand NF-κB-mediated gene expression in more depth.

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Age-associated changes in gene expression in skeletal muscle of healthy individuals reflect accumulation of damage and compensatory adaptations to preserve tissue integrity. To characterize these changes, RNA was extracted and sequenced from muscle biopsies collected from 53 healthy individuals (22–83 years old) of the GESTALT study of the National Institute on Aging–NIH. Expression levels of 57,205 protein-coding and non-coding RNAs were studied as a function of aging by linear and negative binomial regression models. From both models, 1134 RNAs changed significantly with age. The most differentially abundant mRNAs encoded proteins implicated in several age-related processes, including cellular senescence, insulin signaling, and myogenesis. Specific mRNA isoforms that changed significantly with age in skeletal muscle were enriched for proteins involved in oxidative phosphorylation and adipogenesis. Our study establishes a detailed framework of the global transcriptome and mRNA isoforms that govern muscle damage and homeostasis with age.

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The NF-kappaB family of transcription factors regulates genes that are critical for inflammation and immunity. In most cells, NF-kappaB function is induced upon activation of cells by various stimuli. However, constitutive NF-kappaB activity is an equally important aspect of NF-kappaB function that is particularly relevant to chronic inflammation and cancer. Here, we provide a brief overview of NF-kappaB biology and discuss the role of NF-kappaB in mediating the anti-inflammatory effects of tocotrienols The NF-kappaB family of transcription factors is a central player in the regulation of inflammation and immune responses. Consequently, NF-kappaB dysregulation has been implicated in diverse human pathologies ranging from autoimmune diseases to cancers. Additionally, there is considerable interest in the contribution of NF-kappaB-mediated chronic inflammation in aging. Because NF-kappaB-dependent gene regulation is important in virtually all mammalian cell types, it is critical to keep in mind some basic features of its functions when considering interventional therapeutics.