Pre-assembly of STAT4 with the human IFN-alpha/beta receptor-2 subunit is mediated by the STAT4 N-domain.
ABSTRACT CD4(+) T cells regulate adaptive responses to pathogens by secreting unique subsets of cytokines that mediate inflammatory processes. The innate cytokines IL-12 and IFN-alpha/beta regulate type I responses and promote acute IFN-gamma secretion through the activation of the STAT4 transcription factor. Although IL-12-induced STAT4 activation is a conserved pathway across species, IFN-alpha/beta-dependent STAT4 phosphorylation does not occur as efficiently in mice as it does in human T cells. In order to understand this species-specific pathway for IFN-alpha/beta-dependent STAT4 activation, we have examined the molecular basis of STAT4 recruitment by the human IFNAR. In this report, we demonstrate that the N-domain of STAT4 interacts with the cytoplasmic domain of the human, but not the murine IFNAR2 subunit. This interaction mapped to a membrane-proximal segment of the hIFNAR2 spanning amino acids 299-333. Deletion of this region within the hIFNAR2 completely abolishes IFN-alpha/beta-dependent STAT4 tyrosine phosphorylation when expressed in human IFNAR2-deficient fibroblasts. Thus, the human IFNAR2 cytoplasmic domain serves to link STAT4 to the IFNAR as a pre-assembled complex that facilitates cytokine-driven STAT4 activation.
Full-textDOI: · Available from: David Farrar, Jul 07, 2015
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ABSTRACT: Objectives To analyse the influence of IFNα on TNFα production by human peripheral blood mononuclear cells (PBMCs), as well as the possible interference of this cytokine on the effect of antimalarial drugs, TNFα regulators widely used in the treatment of systemic lupus erythematosus (SLE). Methods PBMCs, monocytes or T cells were treated with IFNα alone or simultaneously to cellular stimuli as well as in the presence or absence of chloroquine. Supernatants from such cultures were collected to quantify TNFα by ELISA. TNFα and STAT4 expression in cultured cells were analysed by intracellular flow cytometry. In addition, STAT4 gene expression and serum levels of TNFα and IFNα were quantified in 53 SLE patients and 45 controls. Results IFNα alone did not modify significantly TNFα production, but an increase was observed in stimulated PBMC. Further analyses showed that monocytes were the cellular population responsible for this effect. In addition, IFNα treatment increased STAT4 in stimulated monocytes, suggesting that TNFα upregulation could be mediated by STAT4. On the other hand, the analysis of the antimalarial effect showed that chloroquine was able to inhibit in vitro the expression of TNFα and STAT4 enhanced by IFNα. In antimalarial-treated SLE patients, however, only those with high IFNα serum levels presented lower expression of STAT4. Conclusions IFNα treatment enhances the induction of TNFα and STAT4 in stimulated monocytes, an effect inhibited in vitro by chloroquine treatment. However, the consequence of antimalarial treatment on SLE patients could be different depending on their IFNα serum levels.Cytokine 05/2014; 67(1):13–20. DOI:10.1016/j.cyto.2014.02.002 · 2.87 Impact Factor
Conference Paper: An amplifier predistort lineariser for future mobile radio basestations[Show abstract] [Hide abstract]
ABSTRACT: The linearisation of a radio basestation amplifier using a third order and a fifth order predistortion scheme is studied. Adaptive predistortion using a third order predistorter improves the power level of the inter-modulation distortion (IMD), which results from amplitude and phase nonlinearities in the amplifier frequency response, by between 6.5 dB and 30 dB, as measured by a two-tone simulation test by exciting the input with a sinusoidal waveform. To keep the sampling rate, as low as possible for speeding up the computation time, the RF carrier signal is avoided since it would have no effect on the simulation results; hence frequency down-conversion to baseband is considered. The variation in improvement is due to changes in the input power level. The improvement increases as the input power is backed off from the 1 dB compression point. A fifth order predistorter will give an IMD improvement of between 17 dB and 45 dB if properly adjustedRadio Science Conference, 1996. NRSC '96., Thirteenth National; 04/1996
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ABSTRACT: Particles in 3 to 0.2 mole SiO2/L aqueous Na-silicate solutions are only partially dissociated. Their average molweight (AMW) varies with their Na/Si ratio and concentration. Combined molecular spectroscopic and AMW measurements suggest that only some of the most diluted solutions contain overwhelmingly monomer silicate anions and the average silicate particles contain more than 10 [SiO4] tetrahedral units in some of the more concentrated solutions. Both the dissociation and the hydrolysis affect the FTIR and Raman spectra of dissolved silicates making the revision of some earlier band assignments necessary.Studies in surface science and catalysis 01/2007; 170A:800. DOI:10.1016/S0167-2991(07)80924-4