Background and purpose: P2X 7 is a membrane receptor for extracellular ATP which is highly expressed in dendritic cells, macrophages and microglia where it mediates pro-inflammatory responses. The antibiotic polymyxin B, which binds to and neutralizes the toxic residue of bacterial lipopolysaccharide, greatly amplifies cellular responses mediated by the P2X 7 receptor. However, the molecular mechanism involved is so far unknown. Experimental approach: We investigated the effects of polymyxin B and polymyxin B nonapeptide (PMBN) which is the deacylated amino derivative of polymyxin B lacking the N-terminal fatty amino acid 6-methylheptanoic/octanoic-Dab residue, in human macrophages and HEK293 cells stably expressing the human P2X 7 receptor (HEK293-hP2X 7 ). Differences between the two antibiotics were assessed by monitoring the following: nucleotide-induced cytoplasmic free Ca 2 þ concentration changes, plasma membrane permeability changes, lactate dehydrogenase activity, cell morphology changes. Western blot and microscopic analyses of P2X 7 GFP-expressing cells were also performed. Key results: In contrast to polymyxin B, the polymyxin B nonapeptide was unable to potentiate: a) the ATP-induced Ca 2 þ increase, b) pore formation and consequently ATP-mediated plasma membrane permeabilization; c) ATP-dependent cytotoxicity. Moreover, in contrast to polymyxin B, polymyxin B nonapeptide did not affect aggregation of the P2X 7 receptor subunits and it did not potentiate P2X 7 -dependent cell fusion. Conclusions and Implications: The effects of polymyxin B depended on the presence of its N-terminal fatty amino acid 6-methylheptanoic/octanoic-Dab residue as deletion of this residue abolished polymyxin B-dependent modulation of ATP-triggered responses. These findings are important in the search for allosteric modulators of the P2X 7 receptor.
Abstract. In 3737 subjects without clinically thyroid disorders we evaluated the incidence of thyroid microsomal and thyroglobulin antibodies. These autoantibodies were found in 7% of a normal population, in 9% of patients with various non-autoimmune diseases, and in 11–16% of groups who either had or were at risk for autoimmune diseases: patients with IDDM, vitiligo, alopecia areata, idiopathic hypoparathyroidism, Addison's disease, and first-degree relatives of IDDM patients. Functional thyroid evaluation with TRH test was performed in 197 seropositive subjects and 144 seronegative controls. One-quarter (26%) of the subjects with thyroid autoantibodies showed functional abnormalities on TRH testing, whereas only 2.8% of the 144 seronegative controls showed subclinical hypothyroidism. After an observation period of 12–44 months, 102 persistently seropositive subjects were reassessed and 31% of them showed an impairment in TRH test response.
Dendritic cells (DCs) activate and shape the adaptive immune response by capturing antigens, migrating to peripheral lymphoid organs where naïve T cells reside, expressing high levels of MHC and costimulatory molecules and secreting cytokines and chemokines. DCs are endowed with a high degree of functional plasticity and their functions are tightly regulated. Besides initiating adaptive immune responses, DCs play a key role in maintaining peripheral tolerance toward self-antigens. On the basis of the information gathered from the tissue where they reside, DCs adjust their functional activity to ensure that protective immunity is favoured while unwanted or exaggerated immune responses are prevented. A wide variety of signals from neighbouring cells affecting DC functional activity have been described. Here we will discuss the complex role of extracellular nucleotides in the regulation of DC function and the role of P2 receptors as possible tools to manipulate immune responses.
The iron flux-return structure for the SLC Large Detector (SLD) has' been instrumented with plastic streamer tubes covering an area of about 4500 square meters, to provide muon identification plus energy measurement of hadron showers. A description is given of the production techniques used to construct this large detector system, with an emphasis on the methods by which high reliability and a small number of defects in the completed assembly were ensured.
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