96 research outputs found

    LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L

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    The linear ubiquitin chain assembly complex (LUBAC), composed of HOIP, HOIL-1 and SHARPIN, is required for optimal TNF-mediated gene activation and to prevent cell death induced by TNF. Here, we demonstrate that keratinocyte-specific deletion of HOIP or HOIL-1 (E-KO) results in severe dermatitis causing postnatal lethality. We provide genetic and pharmacological evidence that the postnatal lethal dermatitis in HoipE-KO and Hoil-1E-KO mice is caused by TNFR1-induced, caspase-8-mediated apoptosis that occurs independently of the kinase activity of RIPK1. In the absence of TNFR1, however, dermatitis develops in adulthood, triggered by RIPK1-kinase-activity-dependent apoptosis and necroptosis. Strikingly, TRAIL or CD95L can redundantly induce this disease-causing cell death, as combined loss of their respective receptors is required to prevent TNFR1-independent dermatitis. These findings may have implications for the treatment of patients with mutations that perturb linear ubiquitination and potentially also for patients with inflammation-associated disorders that are refractory to inhibition of TNF alone

    The Receptor Tyrosine Kinase FGFR4 Negatively Regulates NF-kappaB Signaling

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    NFκB signaling is of paramount importance in the regulation of apoptosis, proliferation, and inflammatory responses during human development and homeostasis, as well as in many human cancers. Receptor Tyrosine Kinases (RTKs), including the Fibroblast Growth Factor Receptors (FGFRs) are also important in development and disease. However, a direct relationship between growth factor signaling pathways and NFκB activation has not been previously described, although FGFs have been known to antagonize TNFα-induced apoptosis. assays. FGF19 stimulation of endogenous FGFR4 in TNFα-treated DU145 prostate cancer cells also leads to a decrease in IKKβ activity, concomitant reduction in NFκB nuclear localization, and reduced apoptosis. Microarray analysis demonstrates that FGF19 + TNFα treatment of DU145 cells, in comparison with TNFα alone, favors proliferative genes while downregulating genes involved in apoptotic responses and NFκB signaling.These results identify a compelling link between FGFR4 signaling and the NFκB pathway, and reveal that FGFR4 activation leads to a negative effect on NFκB signaling including an inhibitory effect on proapoptotic signaling. We anticipate that this interaction between an RTK and a component of NFκB signaling will not be limited to FGFR4 alone

    A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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    Corticosteroids in ophthalmology : drug delivery innovations, pharmacology, clinical applications, and future perspectives

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    Micelle assisted morphological evolution of silver nanoparticles

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    Silver nanocrystals are prepared in size and shape selective anionic micelles comprising the surfactant, sodium dodecyl sulfate (SDS). Rod-like micelles of variable lengths were obtained by the addition of a hydrophobic salt, anilinium nitrate that adsorbs on the surface of the micelles thereby modifying its morphology. In this report, we investigate the effect of key parameters of the micelles namely, size and shape of the micelles on the morphology of silver nanocrystals formed. The axial ratio of the rod-like micelles was estimated from dynamic light scattering (DLS) measurements and the resulting silver particles, synthesized in the micellar medium, were characterized by optical absorption, DLS and transmission electron microscopy (TEM).© Elsevie
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