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    ABSTRACT: The interleukin-1 gene cluster occupies a 360 kb region of chromosome 2q13 and contains nine homologous genes. These include agonists and antagonists of the parallel IL-1 and IL-36 systems, and IL1F7, the gene encoding IL-37. As the genes of the cluster are structurally and functionally related and have similar mRNA kinetics, we have sought evidence for gene induction-specific looping of chromatin in the IL-1 cluster by chromatin conformation capture (3C). We show here that IL1A, IL1B and IL1F7 regulatory regions come in close proximity in LPS stimulated cells but not in resting human monocytes. This suggests that IL1A, IL1B and IL1F7 are likely transcribed by the same transcription factory. One cardinal function of transcriptional Locus Control Region (LCR) is bringing map-distant activated genes into close physical proximity within the transcription factory. Our data show distant intergenic DNA segments are also in close proximity to the regulatory regions of the three genes. This may indicate that they are co-regulated and raise the possibility of a LCR within the cluster.
    Cytokine 01/2014; 68(1):16–22.
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    The Journal of infection 12/2013; DOI:10.1016/j.jinf.2013.12.009
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    ABSTRACT: The activation of the complement cascade, a cornerstone of the innate immune response, produces a number of small (74-77 amino acid) fragments, originally termed anaphylatoxins, that are potent chemoattractants and secretagogues that act on a wide variety of cell types. These fragments, C5a, C4a, and C3a, participate at all levels of the immune response and are also involved in other processes such as neural development and organ regeneration. Their primary function, however, is in inflammation, so they are important targets for the development of anti-inflammatory therapies. Only three receptors for complement peptides have been found, but there are no satisfactory antagonists as yet, despite intensive investigation. In humans, there is a single receptor for C3a (C3a receptor), no known receptor for C4a, and two receptors for C5a (C5a(1) receptor and C5a(2) receptor). The most recently characterized receptor, the C5a(2) receptor (previously known as C5L2 or GPR77), has been regarded as a passive binding protein, but signaling activities are now ascribed to it, so we propose that it be formally identified as a receptor and be given a name to reflect this. Here, we describe the complex biology of the complement peptides, introduce a new suggested nomenclature, and review our current knowledge of receptor pharmacology.
    Pharmacological reviews 12/2013; 65(1):500-43. DOI:10.1124/pr.111.005223
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    ABSTRACT: Neutrophil (PMN) lifespan and function are regulated by hypoxia, via components of the HIF/VHL/hydroxylase pathway, including specific roles for hypoxia inducible factor-1α (HIF-1α) and prolyl hydroxylase-3 (PHD3). HIF-2α has both distinct and overlapping biological roles with HIF-1α, and has not previously been studied in the context of neutrophil biology. We have investigated the role of HIF-2α in regulating key PMN functions. Human and murine peripheral blood PMN expressed HIF-2α, with expression up-regulated by acute and chronic inflammatory stimuli and in disease-associated inflammatory PMN. HIF2A gain-of-function mutations resulted in a reduction in PMN apoptosis both ex vivo, through the study of patient cells, and in vivo in a zebrafish tail injury model. In contrast, HIF-2α deficient murine inflammatory PMN displayed increased sensitivity to nitrosative stress induced apoptosis ex vivo and increased PMN apoptosis in vivo, resulting in a reduction in neutrophilic inflammation and reduced tissue injury. Expression of HIF-2α was temporally dissociated from HIF-1α in vivo and predominated in the resolution phase of inflammation. These data support a critical and selective role for HIF-2α in persistence of neutrophilic inflammation, and provide a platform to dissect the therapeutic utility of targeting HIF-2α in chronic inflammatory diseases.
    Blood 11/2013; 123(3). DOI:10.1182/blood-2013-05-500207
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    ABSTRACT: The IMPC (International Mouse Phenotyping Consortium) was launched recently, and its aim is to develop and phenotype mouse knockouts of 4000 genes over the next 5 years and, ultimately, of all 20000 or so genes in the mouse genome. As part of the IMPC, the MRC (Medical Research Council) also launched a call for MRC mouse networks, where groups of U.K.-based researchers could form a consortium based around a particular area of research. Members of the respiratory research community formed the RDDRC (Respiratory Development and Disease Research Consortium) to consolidate and develop respiratory phenotyping methods suitable for high-throughput screening. This paper, arising from a Biochemical Society workshop held in London in 2012, highlights the purposes of the RDDRC and the needs of the respiratory research community.
    Clinical Science 11/2013; 125(10):495-500. DOI:10.1042/CS20130274
  • Thorax 09/2013; 68(12). DOI:10.1136/thoraxjnl-2013-204179
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    ABSTRACT: OBJECTIVE: To investigate the interrelationships among smoking, protein tyrosine phosphatase non-receptor 22 (PTPN22) R620W (rs2476601) genotype, and anticitrullinated peptide antibody (ACPA) status; and among smoking, PTPN22 R620W genotype, and presence of bone erosions overall and separately by ACPA status in patients with rheumatoid arthritis (RA). METHODS: Six studies totaling 2680 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating ACPA status and up to 8 studies totaling 3172 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating presence of erosive damage. RESULTS: Evidence was found for an increase in the odds of ACPA positivity for ever smoking (OR 1.56, 95% CI 1.28-1.90, p = 8.5 × 10(-6)), carriage of at least 1 of the PTPN22 risk alleles (OR 1.50, 95% CI 1.13-2.00, p = 5.5 × 10(-3)) and both ever smoking and carriage of at least 1 of the PTPN22 risk alleles (OR 2.22, 95% CI 1.69-2.91, p = 8.3 × 10(-9)). There was no evidence of an association between presence of erosive damage and smoking status or carriage of PTPN22 risk alleles when analyzed overall or separately by ACPA status. CONCLUSION: This metaanalysis indicates that both smoking and the PTPN22 risk allele are associated with the risk of ACPA positivity. There was insufficient evidence to establish a relationship in either direction between PTPN22 and smoking with erosive damage, despite evidence that ACPA positivity is associated with erosive damage.
    The Journal of Rheumatology 05/2013; 40(7). DOI:10.3899/jrheum.120784
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    ABSTRACT: Macrophages play an essential role in tissue homeostasis, innate immunity, inflammation, and wound repair. Macrophages are also essential during development, severely limiting the use of mouse models in which these cells have been constitutively deleted. Consequently, we have developed a transgenic model of inducible macrophage depletion in which macrophage-specific induction of the cytotoxic diphtheria toxin A chain (DTA) is achieved by administration of doxycycline. Induction of the DTA protein in transgenic animals resulted in a significant 50% reduction in CD68+ macrophages of the liver, spleen, and bone over a period of 6 weeks. Pertinently, the macrophages remaining after doxycycline treatment were substantially smaller and are functionally impaired as shown by reduced inflammatory cytokine production in response to lipopolysaccharide. This inducible model of macrophage depletion can now be utilized to determine the role of macrophages in both development and animal models of chronic inflammatory diseases. genesis 2012. © 2012 Wiley Periodicals, Inc.
    genesis 01/2013; 51(1). DOI:10.1002/dvg.22343
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    ABSTRACT: Despite being initially identified in mice, little is known about the sites of production of members of the BPI fold (BPIF) containing (PLUNC) family of putative innate defence proteins in this species. These proteins have largely been considered to be specificaly expressed in the respiratory tract, and we have recently shown that they exhibit differential expression in the epithelium of the proximal airways. In this study, we have used species-specific antibodies to systematically localize two members of this protein family; BPIFA1 (PLUNC/SPLUNC1) and BPIFB1 (LPLUNC1) in adult mice. In general, these proteins exhibit distinct and only partially overlapping localization. BPIFA1 is highly expressed in the respiratory epithelium and Bowman’s glands of the nasal passages, whereas BPIFB1 is present in small subset of goblet cells in the nasal passage and pharynx. BPIFB1 is also present in the serous glands in the proximal tongue where is co-localised with the salivary gland specific family member, BPIFA2E (parotid secretory protein) and also in glands of the soft palate. Both proteins exhibit limited expression outside of these regions. These results are consistent with the localization of the proteins seen in man. Knowledge of the complex expression patterns of BPIF proteins in these regions will allow the use of tractable mouse models of disease to dissect their function. Electronic supplementary material The online version of this article (doi:10.1007/s00441-012-1490-9) contains supplementary material, which is available to authorized users.
    Cell and Tissue Research 12/2012; 350(3-3):455-464. DOI:10.1007/s00441-012-1490-9
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    ABSTRACT: Anti-adhesion therapies for bacterial infections offer an alternative to antibiotics, with those therapies bacteria are not killed but are prevented from causing harm to a host by inhibiting adherence to host cells and tissues, a prerequisite for the majority of infectious diseases. The mechanisms of these potential therapeutic agents include inhibition of adhesins and their host receptors, vaccination with adhesins or analogs, use of probiotics and dietary supplements that interfere with receptor-adhesin interactions, subminimal inhibitory concentrations of antibiotics and manipulation of hydrophobic interactions. Once developed, these drugs will contribute to the arsenal for fighting infectious disease in the future, potentially subverting antibiotic resistance.
    Expert Review of Anticancer Therapy 12/2012; 10(12):1457-68. DOI:10.1586/eri.12.145
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