Functional Analysis of a Dominant Negative Mutation of Interferon Regulatory Factor 5

BACKGROUND: Interferon regulatory factor (IRF) family members have been implicated as critical transcription factors that function in immune response, hematopoietic differentiation and cell growth regulation. Activation of IRF-5 results in the production of pro-inflammatory cytokines such as TNFalpha, IL6 and IL12p40, as well as type I interferons. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we identify a G202C (position relative to translation start codon) missense-mutation transcript of IRF-5 in transformed B and T cell lines, which were either infected or non-infected by viruses, and peripheral blood from ATL or CLL patients. The mutated transcript encodes a novel protein in which the sixty-eighth amino acid, Alanine, is substituted by Proline (IRF-5P68) in the DNA binding domain of IRF-5. IRF-5P68 phenotype results in a complete loss of its DNA-binding activity and functions as a dominant negative molecule through interacting with wild type IRF-5. Co-expression of IRF-5P68 inhibits MyD88-mediated IRF-5 transactivation. Moreover, Toll-like receptor (TLR)-dependent IL6 and IL12P40 production induced by lipopolysaccharide (LPS), R837 or CpG ODN 1826 was reduced in IRF-5 (P68) expressing cells as compared to the control cells. CONCLUSION: IRF-5P68 acts as a dominant negative regulator that interferes with IRF-5-mediated production of pro-inflammatory cytokines. The functional characterization of the novel IRF-5 mutant in transformed B and T cell lines and in ATL and CLL patients may lead to a better understanding of the role of these transcriptional regulators in hematopoietic malignancies

Gene Expression during the Generation and Activation of Mouse Neutrophils: Implication of Novel Functional and Regulatory Pathways

As part of the Immunological Genome Project (ImmGen), gene expression was determined in unstimulated (circulating) mouse neutrophils and three populations of neutrophils activated in vivo, with comparison among these populations and to other leukocytes. Activation conditions included serum-transfer arthritis (mediated by immune complexes), thioglycollate-induced peritonitis, and uric acid-induced peritonitis. Neutrophils expressed fewer genes than any other leukocyte population studied in ImmGen, and down-regulation of genes related to translation was particularly striking. However, genes with expression relatively specific to neutrophils were also identified, particularly three genes of unknown function: Stfa2l1, Mrgpr2a and Mrgpr2b. Comparison of genes up-regulated in activated neutrophils led to several novel findings: increased expression of genes related to synthesis and use of glutathione and of genes related to uptake and metabolism of modified lipoproteins, particularly in neutrophils elicited by thioglycollate; increased expression of genes for transcription factors in the Nr4a family, only in neutrophils elicited by serum-transfer arthritis; and increased expression of genes important in synthesis of prostaglandins and response to leukotrienes, particularly in neutrophils elicited by uric acid. Up-regulation of genes related to apoptosis, response to microbial products, NFkB family members and their regulators, and MHC class II expression was also seen, in agreement with previous studies. A regulatory model developed from the ImmGen data was used to infer regulatory genes involved in the changes in gene expression during neutrophil activation. Among 64, mostly novel, regulatory genes predicted to influence these changes in gene expression, Irf5 was shown to be important for optimal secretion of IL-10, IP-10, MIP-1α, MIP-1β, and TNF-α by mouse neutrophils in vitro after stimulation through TLR9. This data-set and its analysis using the ImmGen regulatory model provide a basis for additional hypothesis-based research on the importance of changes in gene expression in neutrophils in different conditions

Pressure-induced disappearance of the local rhombohedral distortion in BaTiO3.

BaTiO has been studied by X-ray absorption spectroscopy at the Ti K edge up to 19GPa in a diamond anvil cell at room temperature. The pre-edge features observed at the Ti K edge are sensitive to the pressure. It is shown that the high-pressure cubic phase obtained above 2GPa is similar to the high-temperature one, with titanium out of the centre of the oxygen octahedron. Between 2 and 10GPa the intensity of the pre-edge features decreases indicating that the Ti atom is moving toward the centre of the oxygen octahedron. Above 10GPa, the features do not change anymore, showing that the Ti atom is at the centre of the oxygen octahedron. No correlation between the Ti atom position and the Raman activity under pressure is observed

Direct evidence for oscillatory screening in the quantum Hall effect regime

Oscillations of magneto-donor binding energies are observed in photoluminescence spectra of modulation-doped $\rm GaAs/Ga_{0.67}Al_{0.33}As$ heterostructure. Both the experiment and the underlying theory provide direct evidence for an oscillatory screening of the Coulomb interaction by two-dimensional electron gas in the quantum Hall effect regime

X-ray absorption spectroscopy on titanate perovskites at the Ti K edge

The Ti K edge X-ray absorption has been measured under high pressure at room temperature for ATiO3 perovskites (A = Ca, Sr, Ba and Pb). The pre-edge features have been used to determine the local distortion around the Ti atom as a function of applied features. The ferroelectric local instability decreases when pressure is increased (PbTiO3 ) and eventually vanishes at high pressure (BaTiO3 ). The antiferrodistorsive instability remains unchanged under pressure for CaTiO3 and appears above 5 GPa for SrTiO3 . Moreover, it is shown that at room pressure SrTiO3 was locally ferroelectric. A new phase appears for SrTiO3 above 14 GPa with a strong deformation of the oxygen octahedron