Mechanisms of Legionella pneumophila-induced interleukin-8 expression in human lung epithelial cells

Teruya, Hiromitsu; Higa, Futoshi; Akamine, Morikazu; Ishikawa, Chie; Okudaira, Taeko; Tomimori, Koh; Mukaida, Naofumi; Tateyama, Masao; Heuner, Klaus; Fujita, Jiro; Mori, Nozomu

doi:10.1186/1471-2180-7-102

Cited by 26 publications

(28 citation statements)

References 50 publications

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“…Nevertheless, the results regarding TSA and anacardic acid effects on IL-8 expression were qualitatively comparable. Teruya et al (25) found similar IL-8 levels after infecting A549 or NCI-H292 cells. Therefore, observed IL-8 levels are comparable to other in vitro studies of primary lung epithelial cells and cell lines.…”

Section: Discussionmentioning

confidence: 66%

Histone Acetylation and Flagellin Are Essential for Legionella pneumophila-Induced Cytokine Expression

Schmeck

Lorenz

N′Guessan

et al. 2008

The Journal of Immunology

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Legionella pneumophila causes severe pneumonia. Acetylation of histones is thought to be an important regulator of gene transcription, but its impact on L. pneumophila-induced expression of proinflammatory cytokines is unknown. L. pneumophila strain 130b induced the expression of the important chemoattractant IL-8 and genome-wide histone modifications in human lung epithelial A549 cells. We analyzed the IL-8-promoter and found that histone H4 was acetylated and H3 was phosphorylated at Ser10 and acetylated at Lys14, followed by transcription factor NF-κB. Recruitment of RNA polymerase II to the IL-8 promoter corresponded with increases in gene transcription. Histone modification and IL-8 release were dependent on p38 kinase and NF-κB pathways. Legionella-induced IL-8 expression was decreased by histone acetylase (HAT) inhibitor anacardic acid and enhanced by histone deacetylase (HDAC) inhibitor trichostatin A. After Legionella infection, HATs p300 and CREB-binding protein were time-dependently recruited to the IL-8 promoter, whereas HDAC1 and HDAC5 first decreased and later reappeared at the promoter. Legionella specifically induced expression of HDAC5 but not of other HDACs in lung epithelial cells, but knockdown of HDAC1 or 5 did not alter IL-8 release. Furthermore, Legionella-induced cytokine release, promoter-specific histone modifications, and RNA polymerase II recruitment were reduced in infection with flagellin-deletion mutants. Legionella-induced histone modification as well as HAT-/HDAC-dependent IL-8 release could also be shown in primary lung epithelial cells. In summary, histone acetylation seems to be important for the regulation of proinflammatory gene expression in L. pneumophila infected lung epithelial cells. These pathways may contribute to the host response in Legionnaires’ disease.

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Section: Discussionmentioning

confidence: 66%

Histone Acetylation and Flagellin Are Essential for Legionella pneumophila-Induced Cytokine Expression

Schmeck

Lorenz

N′Guessan

et al. 2008

The Journal of Immunology

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“…The capacity of Hsp90 inhibitors to blunt IL-8 production was recently reported in the context of bacterial-and viralinduced inflammation, including Helicobacter pylori-infected gastric epithelial cells (Yeo et al 2004), Legionella pneumophila-infected lung epithelial cells (Teruya et al 2007), Bacteroides fragilis enterotoxin-treated intestinal epithelial cells (Kim et al 2009), and oncogenic herpes virusinfected endothelial cells and fibroblasts (Defee et al 2011). In these experimental studies, Hsp90 inhibitors acted via deactivation of NFκB, a client of Hsp90 and one of the major transcription factors for IL-8 (Hoffmann et al 2002;Salminen et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes

Tukaj

Grüner

Zillikens

et al. 2014

Cell Stress and Chaperones

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Bullous pemphigoid (BP) is the most common subepidermal autoimmune blistering skin disease characterized by autoantibodies against the hemidesmosomal proteins BP180 and BP230. The cell stress chaperone heat shock protein 90 (Hsp90) has been implicated in inflammatory responses, and recent evidence suggests that it represents a novel treatment target in autoimmune bullous diseases. The aim of the study was to investigate the contribution of Hsp90 to the proinflammatory cytokine production in keratinocytes induced by autoantibodies to BP180 from BP patient serum. HaCaT cells were treated with purified human BP or normal IgG in the absence or presence of the Hsp90 blocker 17-DMAG and effects on viability, interleukin 6 (IL-6) and IL-8 (cytokines critical for BP pathology), NFκB (their major transcription factor), and Hsp70 (marker of effective Hsp90 inhibition and potent negative regulator of inflammatory responses) were investigated. We found that BP IgG stimulated IL-6 and IL-8 release from HaCaT cells and that non-toxic doses of 17-DMAG inhibited this IL-8, but not IL-6 secretion in a dose-and time-dependent fashion.

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“…Cianciotto; Northwestern University Medical School, Chicago, USA [31]), strain JR32 (wild type), JR32 DdotA deficient in dot/icm, encoding a protein essential for the type IVB secretion system (kindly provided by H. Shuman; Dept of Microbiology, Columbia University Medical Center, New York, NY, USA), strain Corby (wild-type), Corby DflaA deficient in flagellin (kindly provided by K. Heuner; Robert Koch-Institut, Berlin, Germany), as well as type II secretion system knockout Corby DlspDE [7,32] (also kindly provided by K. Heuner), were routinely grown on buffered charcoalyeast extract agar for 2-3 days at 37uC before use [33]. A549 cells were infected with L. pneumophila with a multiplicity of infection (MOI) of 10 at 37uC and 5% CO 2 .…”

Section: Cell Linesmentioning

confidence: 99%

“…Although L. pneumophila efficiently infects and stimulates lung epithelial cells [4][5][6][7] and GM-CSF has been shown as important for bacteria elimination via phagocytosis, mechanisms of L. pneumophila-induced release of this cytokine are widely unknown.…”

mentioning

confidence: 99%

“…The bacterium enters the human body by aerosol droplets and successfully establishes itself in macrophages and the alveolar epithelium, which normally offer an efficient barrier against infections [3][4][5][6][7]. Among the various putative virulence factors of this pathogen that have been identified to date, the type II (lspDE) and IVB (Dot/Icm) secretion system enables the bacteria to export proteins into the host cell cytoplasm and, therefore, activates diverse cell signaling pathways [8].…”

mentioning

confidence: 99%

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PKCα and PKCϵ differentially regulateLegionella pneumophila-induced GM-CSF

Vardarova

Scharf²,

Lang³

et al. 2009

Eur Respir J

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Legionella pneumophila is an important causative agent of severe pneumonia in humans. The human alveolar epithelium is an effective barrier for inhaled microorganisms and actively participates in the initiation of innate host defense. Although secretion of granulocytemacrophage colony-stimulating factor (GM-CSF) is essential for the elimination of invading Legionella spp., mechanisms of Legionella pneumophila-induced release of this cytokine are widely unknown.In this study, we have demonstrated a toll-like receptor (TLR)2-and TLR5-dependent release of GM-CSF in L. pneumophila-infected human alveolar epithelial cells. GM-CSF secretion was not dependent on the bacteria type II or type IV secretion system. Furthermore, an increase in protein kinase C (PKC) activity, particularly PKCa and PKCe, was noted. Blocking of PKCa and PKCe activity or expression, but not of PKCb, PKCd, PKCg, PKCh, and PKCf, significantly reduced the synthesis of GM-CSF in infected cells. While PKCa was critical for the initiation of a nuclear factorkB-mediated GM-CSF expression, PKCe regulated GM-CSF production via activator protein 1.Thus, differential regulation of GM-CSF, production by PKC isoforms, contributes to the host response in Legionnaires' disease.

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Mechanisms of Legionella pneumophila-induced interleukin-8 expression in human lung epithelial cells

Cited by 26 publications

References 50 publications

Histone Acetylation and Flagellin Are Essential for Legionella pneumophila-Induced Cytokine Expression

Histone Acetylation and Flagellin Are Essential for Legionella pneumophila-Induced Cytokine Expression

Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes

PKCα and PKCϵ differentially regulateLegionella pneumophila-induced GM-CSF

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