Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) exerts a potent cytotoxic activity especially against many tumor cell types such as transformed keratinocytes. The specific role of the different TRAIL receptors in this process, however, is unknown. In this report we examine the role the TRAIL receptors play in both the apoptotic and nonapoptotic responses of HaCaT keratinocytes to leucine zipper TRAIL (LZ-TRAIL). By employing receptor-specific blocking antibodies we demonstrate that TRAIL receptor 1 plays the primary role in mediating caspase activation and apoptosis in HaCaT cells. Furthermore, we show that this receptor mainly mediates nuclear factor kappaB activation and expression of the pro-inflammatory cytokine interleukin-8 and that nuclear factor kappaB activation is critically required for the induction of pro-inflammatory cytokines in response to LZ-TRAIL. Taken together, our data suggest that beside its potent pro-apoptotic role, LZ-TRAIL leads to pro-inflammatory responses that are mainly mediated by TRAIL receptor 1 in HaCaT keratinocytes.
RelB is an unusual member of the Rel/NF-kB family of transcription factors which are involved in oncogenic processes. Due to a relaxed control by the IkBs, the cytosolic NF-kB inhibitors, RelB is constitutively expressed in the nuclei of lymphoid cells. We show here that RelB is inducibly degraded upon activation of T cells in a fashion similar to the IkBs. However, RelB degradation di ers from that of IkBs since it is not induced by TNFa but only by T cell receptor or TPA/ ionomycin stimulation. Moreover, RelB degradation occurs in three steps: (i) after stimulation RelB is rapidly phosphorylated at amino acids Thr84 and Ser552 followed by (ii) an N-terminal cut and, ®nally, (iii) the complete degradation in the proteasomes. Since mutation of the two phosphoacceptor sites to non-acceptor sites abolished RelB phosphorylation in vivo and led to the stabilization of the mutated RelB DM , site-speci®c phosphorylation appears to be a necessary prerequisite for RelB degradation. RelB is a crucial regulator of NFkB-dependent gene expression. Thus, the signal-induced degradation of RelB should be an important control mechanism of NF-kB activity. Oncogene (2001) 20, 8142 ± 8147.
Tumor necrosis factor (TNF)-␣-induced phosphorylation of the IB proteins by the IB kinase (IKK) complex containing IKK-2 and subsequent degradation of the IB proteins are prerequisites for NF-B activation, resulting in the stimulation of a variety of pro-inflammatory target genes. The C-C chemokine eotaxin-1 is a potent chemoattractant for eosinophils and Th2 lymphocytes, may play an important role in the pathogenesis of atopic dermatitis, and acts via binding to its receptor CCR3. To investigate the role of NF-B signaling in the regulation of these genes, we stably expressed a transdominant mutant of IB␣ and a constitutively active mutant of IKK-2 in mouse NIH3T3 fibroblasts. The transdominant IB␣ mutant completely inhibited TNF-␣-mediated induction of both eotaxin-1 and CCR3, whereas expression of constitutively active IKK-2 was sufficient to drive almost full expression of these two genes in the absence of TNF-␣. Moreover, we observed elevated expression levels of CCR3 and eotaxin-1 protein levels in the skin of IB␣-deficient mice characterized by a widespread dermatitis. Finally, using dermal fibroblasts derived from IB␣-deficient mice, we observed elevated basal expression, enhanced inducibility by TNF-␣, and attenuated down-regulation upon TNF-␣ withdrawal of both CCR3 and eotaxin-1 mRNA levels. These results demonstrate that the IKK-2/IB␣/NF-B pathway plays a critical role for CCR3 and eotaxin-1 expression in fibroblasts and suggests a critical link to the pathogenesis of atopic dermatitis.
Venipunctures in children are difficult. Some factors can hardly be influenced, for example, a well-developed subcutaneous fat tissue. Technical devices may help to identify invisible veins. With the help of ultrasound deep peripheral veins on the wrists and ankles can be presented and punctured. Stiff resistance of a child thwarts any successful puncture. Children should therefore be adequately sedated, if cannot be induced by mask. Missing practice venipuncture and inadequate knowledge of appropriate puncture sites can be met easily by practicing and reading.The possibility of intraosseous puncture today is standard of anesthesia care for children. Within in a few seconds, a secure access to the vein system can be created.
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