Analysis of gene expression in human bronchial epithelial cells upon influenza virus infection and regulation by p38 mitogen-activated protein kinase and c-Jun-N-terminal kinase
Division of Respiratory Disease, Department of Internal Medicine, School of Medicine, Nihon University, Tokyo, Japan. Respirology
(Impact Factor: 3.35).
04/2008; 13(2):203-14. DOI: 10.1111/j.1440-1843.2007.01204.x
Airway epithelial cells, which are the initial site of influenza virus (IV) infection, participate in the inflammatory process through the expression of various genes. In this process, mitogen-activated protein kinase (MAPK) may be associated with the expression of many genes, but its precise role remains unknown.
A comprehensive analysis was performed of gene expression in human bronchial epithelial cells upon IV infection, using an Affymetrix gene chip containing 12 000 genes. Regulation of gene expression by MAPK was also analysed.
A total of 5998 genes were detected. Upon IV infection, 165 genes were upregulated and 49 of these were interferon-stimulated genes. The functions of 129 genes, including 14 apoptosis-related genes and 6 antiviral genes, were well characterized; however, those of 36 genes were unknown. The expression of 29 genes was inhibited either by SB 203580, a specific inhibitor of p38 MAPK, or by CEP-11004, a specific inhibitor of the c-Jun-N-terminal kinase (JNK) cascade, and the percentage inhibition by SB 203580 correlated with that by CEP-11004, suggesting that p38 and JNK participate in a common downstream pathway involved in the regulation of gene expression. p38 MAPK- or JNK-dependent genes were functionally classified into diverse categories.
Although further studies are needed to obtain a more complete understanding of gene expression and the role of MAPK in gene expression, the present results are important in understanding the molecular mechanisms involved in the response of bronchial epithelial cells to IV infection.
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Available from: Yvonne M W Janssen-Heininger
- "Our data show that JNK1 deletion results in an altered inflammatory cellular phenotype in the lung and suppression of KC and IL-10 production. A recent microarray study with a JNK1 inhibitor showed decreased Influenza A induced IL-6 production, although in JNK1 −/− mice we did not observe this #. Our data show that JNK1 −/− mice had increased numbers of lymphocytes in the BAL, but no change in the relative proportion of T cells versus WT mice. "
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ABSTRACT: The c-Jun N-terminal kinase (JNK) - 1 pathway has been implicated in the cellular response to stress in many tissues and models. JNK1 is known to play a role in a variety of signaling cascades, including those involved in lung disease pathogenesis. Recently, a role for JNK1 signaling in immune cell function has emerged. The goal of the present study was to determine the role of JNK1 in host defense against both bacterial and viral pneumonia, as well as the impact of JNK1 signaling on IL-17 mediated immunity. Wild type (WT) and JNK1 -/- mice were challenged with Escherichia coli, Staphylococcus aureus, or Influenza A. In addition, WT and JNK1 -/- mice and epithelial cells were stimulated with IL-17A. The impact of JNK1 deletion on pathogen clearance, inflammation, and histopathology was assessed. JNK1 was required for clearance of E. coli, inflammatory cell recruitment, and cytokine production. Interestingly, JNK1 deletion had only a small impact on the host response to S. aureus. JNK1 -/- mice had decreased Influenza A burden in viral pneumonia, yet displayed worsened morbidity. Finally, JNK1 was required for IL-17A mediated induction of inflammatory cytokines and antimicrobial peptides both in epithelial cells and the lung. These data identify JNK1 as an important signaling molecule in host defense and demonstrate a pathogen specific role in disease. Manipulation of the JNK1 pathway may represent a novel therapeutic target in pneumonia.
PLoS ONE 04/2012; 7(4):e34638. DOI:10.1371/journal.pone.0034638 · 3.23 Impact Factor
Available from: Kenneth Baillie
- "This review highlighted the earlier work of Toth et al that identified 75 immune related genes (including 13 interferon related genes and 10 chemokine related genes) that were differentially expressed in C57BL/6J compared to BALB/cByJ mice in response to influenza H3N2 HK-X31 infection . The review also identified increased expression of seven common genes in both H1N1/1918 and H3N2 HK-X31 infection of BALB/c mice, and 17 genes that showed increased expression in both human bronchial epithelial cell lines and mice infected with H3N2 (A/Udon/307/72 human bronchial epithelial cell, HK-X31 mice) , -. The review by Zhang et al proposed a list of around 100 candidate genes that may be related to susceptibility to influenza infection based on existing knowledge of the proteins involved in virus replication and the innate immune response . "
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ABSTRACT: The World Health Organization has identified studies of the role of host genetics on susceptibility to severe influenza as a priority. A systematic review was conducted to summarize the current state of evidence on the role of host genetics in susceptibility to influenza (PROSPERO registration number: CRD42011001380).
PubMed, Web of Science, the Cochrane Library, and OpenSIGLE were searched using a pre-defined strategy for all entries up to the date of the search. Two reviewers independently screened the title and abstract of 1,371 unique articles, and 72 full text publications were selected for inclusion. Mouse models clearly demonstrate that host genetics plays a critical role in susceptibility to a range of human and avian influenza viruses. The Mx genes encoding interferon inducible proteins are the best studied but their relevance to susceptibility in humans is unknown. Although the MxA gene should be considered a candidate gene for further study in humans, over 100 other candidate genes have been proposed. There are however no data associating any of these candidate genes to susceptibility in humans, with the only published study in humans being under-powered. One genealogy study presents moderate evidence of a heritable component to the risk of influenza-associated death, and while the marked familial aggregation of H5N1 cases is suggestive of host genetic factors, this remains unproven.
The fundamental question "Is susceptibility to severe influenza in humans heritable?" remains unanswered. Not because of a lack of genotyping or analytic tools, nor because of insufficient severe influenza cases, but because of the absence of a coordinated effort to define and assemble cohorts of cases. The recent pandemic and the ongoing epizootic of H5N1 both represent rapidly closing windows of opportunity to increase understanding of the pathogenesis of severe influenza through multi-national host genetic studies.
PLoS ONE 03/2012; 7(3):e33180. DOI:10.1371/journal.pone.0033180 · 3.23 Impact Factor
Available from: Philip J Thompson
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ABSTRACT: The year 2006 was a good year for basic science publications in Respirology with a lot of the studies being relevant to clinical practice. In this respect many of the publications focused on biomarkers of disease and so much so that these have been discussed at the end of this review. The majority of manuscripts are related to airway diseases, respiratory infections, interstitial lung diseases and lung cancers, and are discussed under these headings.
Respirology 04/2007; 12(2):184-90. DOI:10.1111/j.1440-1843.2007.01045.x · 3.35 Impact Factor
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