The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4

Macrophages are pivotal constituents of the innate immune system, vital for recognition and elimination of microbial pathogens. Macrophages use Toll-like receptors (TLRs) to detect pathogen-associated molecular patterns--including bacterial cell wall components, such as lipopolysaccharide or lipoteichoic acid, and viral nucleic acids, such as double-stranded (ds)RNA--and in turn activate effector functions, including anti-apoptotic signalling pathways. Certain pathogens, however, such as Salmonella spp., Shigellae spp. and Yersiniae spp., use specialized virulence factors to overcome these protective responses and induce macrophage apoptosis. We found that the anthrax bacterium, Bacillus anthracis, selectively induces apoptosis of activated macrophages through its lethal toxin, which prevents activation of the anti-apoptotic p38 mitogen-activated protein kinase. We now demonstrate that macrophage apoptosis by three different bacterial pathogens depends on activation of TLR4. Dissection of anti- and pro-apoptotic signalling events triggered by TLR4 identified the dsRNA responsive protein kinase PKR as a critical mediator of pathogen-induced macrophage apoptosis. The pro-apoptotic actions of PKR are mediated both through inhibition of protein synthesis and activation of interferon response factor 3.     

Cauchy und Gauβ. Cauchys Rezeption im Umfeld von Gauβ

Ohne ZusammenfassungVorgelegt von M. Folkerts     

Facteurs influençant la fertilité des mâles deXenopus laevis D. (Batracien anoure)

Summary Under the conditions prevailing at the Station de Zoologie expérimentale (University of Geneva), the fertility of males ofXenopus laevis decreases every year in the autumn (Figure). Long-day treatment significantly increases the fertility and leads to the conclusion that the decrease is due to photoperiodic influences. Treatment with Antex (Leo) (i.e. a follicle-ripening hormone) for 3 weeks highly activates spermatogenesis at a time when the gonads normally remain inactive.

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Remerciements: Je dois ma reconnaissance à Mlle K. Ponse, Professeur d'endocrinologie, pour ses conseils et les discussions sur l'effet des différentes hormones gonadotropes; au Professeur A. Linder, Professeur de statistique mathématique, qui a bien voulu faire l'analyse statistique des croisements; et à mes collègues Mme F. Vanderhaeghe, Dr ès sc., et Mlle A. Droin, Dr ès sc., pour leurs observations et discussions. Le travail technique a été effectué avec l'appui du Fonds National Suisse pour la Recherche Scientifique N 2551.     

Characterization of DNA sequences through which cadmium and glucocorticoid hormones induce human metallothionein-IIA gene

Deletion experiments have defined two stretches of DNA (genetic elements), lying close to the promoter for a human gene for metallothionein, that separately mediate the induction of the gene by heavy metal ions, particularly cadmium, and by glucocorticoid hormones. The element responsible for induction by cadmium is duplicated, yet a single copy is fully functional; the element responsible for induction by glucocorticoid hormones is coincident with the DNA-binding site for the glucocorticoid hormone receptor.     

Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase

NF-kappaB is a critical activator of genes involved in inflammation and immunity. Pro-inflammatory cytokines activate the IkappaB kinase (IKK) complex that phosphorylates the NF-kappaB inhibitors, triggering their conjugation with ubiquitin and subsequent degradation. Freed NF-kappaB dimers translocate to the nucleus and induce target genes, including the one for cyclo-oxygenase 2 (COX2), which catalyses the synthesis of pro-inflammatory prostaglandins, in particular PGE. At late stages of inflammatory episodes, however, COX2 directs the synthesis of anti-inflammatory cyclopentenone prostaglandins, suggesting a role for these molecules in the resolution of inflammation. Cyclopentenone prostaglandins have been suggested to exert anti-inflammatory activity through the activation of peroxisome proliferator-activated receptor-gamma. Here we demonstrate a novel mechanism of antiinflammatory activity which is based on the direct inhibition and modification of the IKKbeta subunit of IKK. As IKKbeta is responsible for the activation of NF-kappaB by pro-inflammatory stimuli, our findings explain how cyclopentenone prostaglandins function and can be used to improve the utility of COX2 inhibitors.