Inhibition of NF-κB Activity by Thalidomide through Suppression of IκB Kinase Activity

The sedative and anti-nausea drug thalidomide, which causes birth defects in humans, has been shown to have both anti-inflammatory and anti-oncogenic properties. The anti-inflammatory effect of thalidomide is associated with suppression of cytokine expression and the anti-oncogenic effect with inhibition of angiogenesis. It is presently unclear whether the teratogenic properties of thalidomide are connected in any way to the beneficial, anti-disease characteristics of this drug. The transcription factor NF-κB has been shown to be a key regulator of inflammatory genes such as tumor necrosis factor-α and interleukin-8. Inhibition of NF-κB is associated with reduced inflammation in animal models, such as those for rheumatoid arthritis. We show here that thalidomide can block NF-κB activation through a mechanism that involves the inhibition of activity of the IκB kinase. Consistent with the observed inhibition of NF-κB, thalidomide blocked the cytokine-induced expression of NF-κB-regulated genes such as those encoding interleukin-8, TRAF1, and c-IAP2. These data indicate that the therapeutic potential for thalidomide may be based on its ability to block NF-κB activation through suppression of IκB kinase activity

NF-κB and IκBα are found in the mitochondria. Evidence for regulation of mitochondrial gene expression by NF-κB

The transcription factor NF-κB has been shown to be predominantly cytoplasmically localized in the absence of an inductive signal. Stimulation of cells with inflammatory cytokines such as tumor necrosis factor α or interleukin-1 induces the degradation of IκB, the inhibitor of NF-κB, allowing nuclear accumulation of NF-κB and regulation of specific gene expression. The degradation of IκB is controlled initially by phosphorylation induced by the IκB kinase, which leads to ubiquitination and subsequent proteolysis of the inhibitor by the proteasome. We report here that NF-κB and IκBα (but not IκBβ) are also localized in the mitochondria. Stimulation of cells with tumor necrosis factor α leads to the phosphorylation of mitochondrial IκBα and its subsequent degradation by a nonproteasome-dependent pathway. Interestingly, expression of the mitochondrially encoded cytochrome c oxidase III and cytochrome b mRNAs were reduced by cytokine treatment of cells. Inhibition of activation of mitochondrial NF-κB by expression of the superrepressor form of IκBα inhibited the loss of expression of both cytochrome c oxidase III and cytochrome b mRNA. These data indicate that the NF-κB regulatory pathway exists in mitochondria and that NF-κB can negatively regulate mitochondrial mRNA expression

Fitting the integrated Spectral Energy Distributions of Galaxies

Fitting the spectral energy distributions (SEDs) of galaxies is an almost universally used technique that has matured significantly in the last decade. Model predictions and fitting procedures have improved significantly over this time, attempting to keep up with the vastly increased volume and quality of available data. We review here the field of SED fitting, describing the modelling of ultraviolet to infrared galaxy SEDs, the creation of multiwavelength data sets, and the methods used to fit model SEDs to observed galaxy data sets. We touch upon the achievements and challenges in the major ingredients of SED fitting, with a special emphasis on describing the interplay between the quality of the available data, the quality of the available models, and the best fitting technique to use in order to obtain a realistic measurement as well as realistic uncertainties. We conclude that SED fitting can be used effectively to derive a range of physical properties of galaxies, such as redshift, stellar masses, star formation rates, dust masses, and metallicities, with care taken not to over-interpret the available data. Yet there still exist many issues such as estimating the age of the oldest stars in a galaxy, finer details ofdust properties and dust-star geometry, and the influences of poorly understood, luminous stellar types and phases. The challenge for the coming years will be to improve both the models and the observational data sets to resolve these uncertainties. The present review will be made available on an interactive, moderated web page (sedfitting.org), where the community can access and change the text. The intention is to expand the text and keep it up to date over the coming years.Comment: 54 pages, 26 figures, Accepted for publication in Astrophysics & Space Scienc