Members of the NF-κB transcription factor family play a critical role in the development of innate immunity. Upon recognition of pathogen infections or tissue damage, the NF-κB pathway is strongly activated by cellular pattern recognition receptors, including Toll-like receptors and multiple cytosolic receptors such as RIG-I-like helicases and NOD family proteins. NF-κB is required not only for the expression, but also for subsequent signal transduction of numerous downstream cytokines. NF-κB-responsive genes affect a diverse array of cellular processes including apoptosis and cell survival, and often directly control the course of a pathogen infection. In this review, we will examine signaling pathways leading to NF-κB activation during the innate immune response and mechanisms of pathogen-modulation of these pathways; the specifics of NF-κB-dependent gene programs, and the physiological consequences for the immune system caused by the absence of individual NF-κB subunits.

M uch effort has gone towards crafting mandates and standards for researchers to share their data 1-3. Considerably less time has been spent measuring just how valuable data sharing is, or recognizing the scientific contributions of the people responsible for those data sets. The impact of research continues to be measured by primary publications, rather than by subsequent uses of the data. To incentivize the sharing of useful data, the scientific enterprise needs a well-defined system that links individuals with reuse of data sets they generate 4. To further this Microscopy images of normal and cancerous human tissue-when reused by others, the impact of the collected data is multiplied.

Detection of viral genomes by the innate immune system elicits an antiviral gene program mediated by type I interferons (IFNs). While viral RNA and DNA species induce IFN via separate pathways, the mechanisms by which these pathways are differentially modulated are unknown. Here we show that the positive regulator of IFN in the RNA pathway, TRAF3, has an inhibitory function in the DNA pathway. Loss of TRAF3 coincides with increased expression of the alternative NF-κB-inducing molecule, NIK, which interacts with the DNA pathway adaptor, STING, to enhance IFN induction. Cells lacking NIK display defective IFN activation in the DNA pathway due to impaired STING signaling, and NIK-deficient mice are more susceptible to DNA virus infection. Mechanistically, NIK operates independently from alternative NF-κB signaling components and instead requires autophosphorylation and oligomerization to activate STING. Thus a previously undescribed pathway for NIK exists in activating IFN in the DNA pathway.

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Indole-3-carbinol (I3C), a naturally occurring compound found in vegetables of the Brassica genus, such as broccoli and cabbage, is a promising anticancer agent previously shown to induce a G(1) cell-cycle arrest in the cells of human lymph node carcinoma of prostate (LNCaP) through regulation of specific G(1)-acting cell-cycle components. Since the androgen receptor (AR) mediates proliferation and differentiation in the prostate and is expressed in nearly all human prostate cancers, the effects of I3C on AR expression and function were examined in LNCaP cells. Immunoblot and quantitative RT-PCR assays revealed that I3C inhibited the expression of AR protein and mRNA levels within 12 h of indole treatment. I3C downregulated the reporter activity of LNCaP cells transiently transfected with an AR promoter-luciferase plasmid, demonstrating that a unique response to I3C is the inhibition of AR promoter activity. In contrast to I3C, the natural I3C dimerization product 3,3'-diindolylmethane, which acts as an androgen antagonist, had no effect on AR expression. To determine the functional significance of the I3C-inhibited expression of AR, the AR-regulated prostate specific antigen (PSA) was utilized as a downstream indicator. I3C downregulated the expression of PSA transcripts and protein levels and inhibited PSA promoter activity, as well as that of a minimal androgen responsive element containing reporter plasmid. Expression of exogenous AR prevented the I3C disruption of androgen-induced PSA expression. Taken together, our results demonstrate that I3C represses AR expression and responsiveness in LNCaP cells as a part of its antiproliferative mechanism.