77 research outputs found
The Inflammasome: First Line of the Immune Response to Cell Stress
The NALP3-inflammasome is a protein complex that stimulates caspase-1 activation to promote the processing and secretion of proinflammatory cytokines. Recent work indicates that the NALP3-inflammasome can be activated by endogenous âdanger signalsâ as well as compounds associated with pathogens (Kanneganti et al., 2006; Mariathasan et al., 2006; Martinon et al., 2006; Sutterwala et al., 2006). Here, we discuss new insights into the regulation of caspase-1 activity in the inflammatory response
The Effect of Grazing on Fecal Shedding of Pathogenic Escherichia coli in Beef Cattle
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Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome
Pseudomonas aeruginosa is a Gram-negative bacterium that causes opportunistic infections in immunocompromised individuals. P. aeruginosa employs a type III secretion system to inject effector molecules into the cytoplasm of the host cell. This interaction with the host cell leads to inflammatory responses that eventually result in cell death. We show that infection of macrophages with P. aeruginosa results in activation of caspase-1 in an IPAF-dependent, but flagellin-independent, manner. Macrophages deficient in IPAF or caspase-1 were markedly resistant to P. aeruginosaâinduced cell death and release of the proinflammatory cytokine interleukin (IL)-1ÎČ. A subset of P. aeruginosa isolates express the effector molecule exoenzyme U (ExoU), which we demonstrate is capable of inhibiting caspase-1âdriven proinflammatory cytokine production. This study shows a key role for IPAF and capase-1 in innate immune responses to the pathogen P. aeruginosa, and also demonstrates that virulent ExoU-expressing strains of P. aeruginosa can circumvent this innate immune response
Induction of Nod2 in Myelomonocytic and Intestinal Epithelial Cells via Nuclear Factor-kB Activation
Nod2, a member of the Apaf1/Nod protein family, confers responsiveness to bacterial products and activates NF-kB, a ranscription factor that plays a central role in innate immunity. Recently, genetic variation in Nod2
has been associated with susceptibility to Crohnâs disease.
Here, we report that expression of Nod2 is induced upon differentiation of CD34+ hematopoietic progenitor cells into granulocyte or monocyte/macrophages. In peripheral
blood cells, the highest levels of Nod2 were
observed in CD14+ (monocytes), CD15+ (granulocytes), and CD40+/CD86+ (dendritic cells) cell populations. Notably, stimulation of myeloblastic and epithelial cells with bacterial lipopolysaccharide or TNF resulted in
up-regulation of Nod2. A search for consensus sites within the Nod2 promoter revealed a NF-kB binding element that was required for transcriptional activity in
response to TNF . Moreover, ectopic expression of p65 induced transactivation, whereas that of dominant-negative I B blocked the transcriptional activity of the
Nod2 promoter. Upon stimulation with TNF or lipopolysaccharide, both p50 and p65 subunits of NF-kB were bound to the Nod2 promoter. Thus, Nod2 expression is enhanced by proinflammatory cytokines and bacterial
components via NF-kB, a mechanism that may contribute to the amplification of the innate immune response and susceptibility to inflammatory disease
Anomalous Transport Properties in BiS2-based Superconductors LnO1âxFxBiS2 (Ln = Nd, La-Sm)
We report the electronic properties of the layered bismuth-based sulfide superconductors NdO1âxFxBiS2 (x = 0.25, 0.4, and 0.5) and La1âySmyO0.5F0.5BiS2 (y = 0.1â0.7), which have been studied by investigation of their transport properties and X-ray diffraction. In the lightly carrier-doped NdO1âxFxBiS2 (x = 0.25 and 0.4) and La1âySmyO0.5F0.5BiS2 (y = 0.3 and 0.4), the resistivity and Hall coefficient exhibit anomalous temperature dependences below TCDW ⌠130 and 200 K, respectively, suggesting the formation of an energy gap on the Fermi surface associated with charge-density wave (CDW). In NdO1âxFxBiS2 (x = 0.25), the bond angles and bond lengths of the BiâS pentahedron change their temperature dependences below âŒ200 K, suggesting that a lattice instability related to the BiâS pentahedron exists below âŒ200 K, which is much higher than TCDW. These results indicate that the lattice instability of the BiâS pentahedron can trigger a CDW transition in the low-carrier region of BiS2 superconductors
Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis
Caspase-1 is activated by a variety of stimuli after the assembly of the âinflammasome,â an activating platform made up of a complex of the NOD-LRR family of proteins. Caspase-1 is required for the secretion of proinflammatory cytokines, such as interleukin (IL)-1ÎČ and IL-18, and is involved in the control of many bacterial infections. Paradoxically, however, its absence has been reported to confer resistance to oral infection by Salmonella typhimurium. We show here that absence of caspase-1 or components of the inflammasome does not result in resistance to oral infection by S. typhimurium, but rather, leads to increased susceptibility to infection
BRCA1 and p53 Tumor Suppressor Molecules in Alzheimerâs Disease
Tumor suppressor molecules play a pivotal role in regulating DNA repair, cell proliferation, and cell death, which are also important processes in the pathogenesis of Alzheimerâs disease. Alzheimerâs disease is the most common neurodegenerative disorder, however, the precise molecular events that control the death of neuronal cells are unclear. Recently, a fundamental role for tumor suppressor molecules in regulating neurons in Alzheimerâs disease was highlighted. Generally, onset of neurodegenerative diseases including Alzheimerâs disease may be delayed with use of dietary neuro-protective agents against oxidative stresses. Studies suggest that dietary antioxidants are also beneficial for brain health in reducing disease-risk and in slowing down disease-progression. We summarize research advances in dietary regulation for the treatment of Alzheimerâs disease with a focus on its modulatory roles in BRCA1 and p53 tumor suppressor expression, in support of further therapeutic research in this field
Neuron Membrane Trafficking and Protein Kinases Involved in Autism and ADHD
A brain-enriched multi-domain scaffolding protein, neurobeachin has been identified as a candidate gene for autism patients. Mutations in the synaptic adhesion protein cell adhesion molecule 1 (CADM1) are also associated with autism spectrum disorder, a neurodevelopmental disorder of uncertain molecular origin. Potential roles of neurobeachin and CADM1 have been suggested to a function of vesicle transport in endosomal trafficking. It seems that protein kinase B (AKT) and cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) have key roles in the neuron membrane trafficking involved in the pathogenesis of autism. Attention deficit hyperactivity disorder (ADHD) is documented to dopaminergic insufficiencies, which is attributed to synaptic dysfunction of dopamine transporter (DAT). AKT is also essential for the DAT cell-surface redistribution. In the present paper, we summarize and discuss the importance of several protein kinases that regulate the membrane trafficking involved in autism and ADHD, suggesting new targets for therapeutic intervention
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