Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin disease

Expression of enzymatically inactive caspase-8, or deletion of caspase-8 from basal epidermal keratinocytes, triggers chronic skin inflammation in mice. Unlike similar inflammation resulting from arrest of nuclear factor κB activation in the epidermal cells, the effect induced by caspase-8 deficiency did not depend on TNF, IL-1, dermal macrophage function, or expression of the toll-like receptor adapter proteins MyD88 or TRIF. Both interferon regulatory factor (IRF) 3 and TANK-binding kinase were constitutively phosphorylated in the caspase-8–deficient epidermis, and knockdown of IRF3 in the epidermis-derived cells from these mice abolished the expression of up-regulated genes. Temporal and spatial analyses of the alterations in gene expression that result from caspase-8 deficiency reveal that the changes are initiated before birth, around the time that cornification develops, and occur mainly in the suprabasal layer. Finally, we found that caspase-8–deficient keratinocytes display an enhanced response to gene activation by transfected DNA. Our findings suggest that an enhanced response to endogenous activators of IRF3 in the epidermis, presumably generated in association with keratinocyte differentiation, contributes to the skin inflammatory process triggered by caspase-8 deficiency

NF-κB: a new player in angiostatic therapy

Angiogenesis is considered a promising target in the treatment of cancer. Most of the angiogenesis inhibitors in late-stage clinical testing or approved for the treatment of cancer act indirectly on endothelial cells. They either neutralize angiogenic growth factors from the circulation or block the signaling pathways activated by these growth factors. Another group of angiogenesis inhibitors are the direct angiostatic compounds. These agents have a direct effect on the endothelium, affecting cellular regulatory pathways, independently of the tumor cells. The reason that this category of agents is lagging behind regarding their translation to the clinic may be the lack of sufficient knowledge on the mechanism of action of these compounds. The transcription factor NF-κB has been recently connected with multiple aspects of angiogenesis. In addition, several recent studies report that angiogenesis inhibition is associated to NF-κB activation. This is of special interest since in tumor cells NF-κB activation has been associated to inhibition of apoptosis and currently novel treatment strategies are being developed based on inhibition of NF-κB. The paradigm that systemic NF-κB inhibition can serve as an anti-cancer strategy, therefore, might need to be re-evaluated. Based on recent data, it might be speculated that NF-κB activation, when performed specifically in endothelial cells, could be an efficient strategy for the treatment of cancer

DHMEQ, a novel NF-kappaB inhibitor, suppresses growth and type I collagen accumulation in keloid fibroblasts

Background:Keloid is a benign dermal tumor characterized by proliferation of dermal fibroblasts and overproduction of extracellular matrix (ECM). Nuclear factor kappaB (NF-κB) plays an important role in regulation of inflammation, immune response and cell proliferation. Activation of the NF-κB pathway is thought to be closely linked to abnormal cell proliferation and ECM production in keloid fibroblasts. Objective:This study was set out to investigate the effects of a novel selective NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on keloid fibroblasts. Methods:Primary normal and keloid dermal fibroblasts were used for this study. NF-κB activity was assessed by DNA-binding assay and immunohistochemistry. The effect of DHMEQ was evaluated by cell viability, cell growth and type I collagen accumulation. Results:Basal NF-κB activity was constitutively elevated in keloid fibroblasts, indicating that this pathway is involved in keloid pathogenesis. DHMEQ markedly reduced cell proliferation and type I collagen accumulation in keloid fibroblasts. Conclusion:The inhibition of NF-κB by DHMEQ may be an attractive therapeutic approach for keloids

Targeting A20 Decreases Glioma Stem Cell Survival and Tumor Growth

The A20 protein is a known inhibitor of apoptosis that here is shown to be a novel cancer stem cell-promoting factor associated with poor glioma patient survival

NF-kB in epidermal signal transduction and tumor development

The transcription factor NF-kappaB has been extensively studied since its discovery. NFkappaB has been shown to be invoved in many cellular processes in many different cell types. However, its functions in skin physiology and epidermal tumor development are largely unknown. In this thesis we have investigated signaling pathways leading to NF-kappaB activation in keratinocytes and studied the function of NF-kappaB in development and carcinogenesis of the skin. We demonstrate that ultraviolet (UV) radiation can act in keratinocytes via TNF receptor 1 and TRAF 2 to elicit Rel protein-DNA binding resulting in enhanced transcription. The signaling induced is ligand independent and is likely to be a major pathway for Rel/NF- kappaB activation by UVB in the skin. We selectively blocked Rel/NF-kappaB activation in the skin by targeted expression of a signal resistant form of IkappaB-alpha in the epidermis of transgenic mice. Our data demonstrate that selective inhibition of Rel/NF-kappaB signaling in epithelial skin cells disrupts normal epidermal homeostasis and hair follicle development, increases the number of keratinocytes undergoing apoptosis and leads to the development of squamous cell carcinoma. In a characterization of the progressive dysplasia leading to squamous cell carcinoma development we observed upregulation of the proinflammatory cytokine TNF-alpha in transgenic skin, associated with a mixed inflammatory cell infiltrate. Furthermore, we show that inhibition of NF-kappaB signaling in mouse skin generates transgenic keratinocytes unable to arrest the cell cycle in response to DNA damage induced by gamma-radiation. In the spontaneous skin tumors that develop in transgenic mice no mutations were found in the Ha-ras or p53 gene, suggesting that inhibition of NFkappaB signaling in skin can induce cancer development independently of initiating mutations in the Ha-ras gene or additional mutations in the p53 gene. In summary, we have identified TNF receptor 1 as a transducer of the UV-signal in the activation of NF-kappaB. We have shown using a transgenic mouse model, that NF-kappaB plays an important part in epidermal proliferation and tumor development. The elucidation of the mechanisms responsible for the tumor development will provide important new knowledge in our understanding of skin carcinogenesis