Mechanisms of<i>Chlamydophila pneumoniae</i>–Mediated GM-CSF Release in Human Bronchial Epithelial Cells

Krüll, Matthias; Bockstaller, Petra; Wuppermann, Frederik N.; Klucken, Andrea C.; Mühling, J.; Schmeck, Bernd; Seybold, Joachim; Walter, Clemens; Maass, Matthias; Rosseau, Simone; Hegemann, Johannes H.; Suttorp, Norbert; Hippenstiel, Stefan

doi:10.1165/rcmb.2004-0157oc

Cited by 29 publications

(26 citation statements)

References 33 publications

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“…In this study, we established the importance of MKK3 and downstream p38 signaling in the cHSP60-induced inflammatory response. This finding is consistent with the previous observation that p38 signaling is essential in Chlamydia pathology (15,23,24). Using a combination of genetic-deletion and pharmacologic-blocking approaches, we defined a specific requirement for p38 in the activation of the nuclear kinase MSK1 and, thereby, NF-kB transcriptional activity.…”

Section: Discussionsupporting

confidence: 90%

“…It was shown that p38 is potentially activated by Chlamydia or cHSP60 in human airway epithelial cells. The activation of p38, but not of ERK, c-Jun kinase/JNK, or PI3K, was required for the activation of NF-kB and the release of GM-CSF (23). A recent report indicated that the inhibition of p38 MAPK led to a 70-90% inhibition in IFN-b expression induced by Chlamydia muridarum.…”

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confidence: 97%

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MAPK Kinase 3 Potentiates Chlamydia HSP60-Induced Inflammatory Response through Distinct Activation of NF-κB

Kang

Wang

Lü

et al. 2013

The Journal of Immunology

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Chlamydia pneumonia (C. pneumonia) remains one of the leading causes of bacterial pneumonia and has been implicated in the pathogenesis of some inflammation-related diseases, such as asthma, chronic obstructive pulmonary disease, and vascular diseases. Heat shock protein 60 is one of the pathogenic components of C. pneumonia that is closely associated with the inflammatory disorders. However, the molecular basis for the immunopathologic property of chlamydial heat shock protein (cHSP60) has not been elucidated. In this article, we report that MAPK kinase 3 (MKK3) is essential for cHSP60-induced lung inflammation, because MKK3-knockout mice displayed significantly reduced lung neutrophil accumulation and decreased production of proinflammatory mediators, correlating with the alleviated inflammatory response in lung tissues. Mechanistically, p38 kinase was selectively activated by MKK3 in response to cHSP60 and activated NF-κB by stimulating the nuclear kinase, mitogen- and stress-activated protein kinase 1. The specific knockdown of mitogen- and stress-activated protein kinase 1 in macrophages resulted in a defective phosphorylation of NF-κB/RelA at Ser276 but had no apparent effect on RelA translocation. Furthermore, TGF-β–activated kinase 1 was found to relay the signal to MKK3 from TLR4, the major receptor that sensed cHSP60 in the initiation of the inflammatory response. Thus, we establish a critical role for MKK3 signaling in cHSP60 pathology and suggest a novel mechanism underlying C. pneumonia–associated inflammatory disorders.

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Section: Discussionsupporting

confidence: 90%

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confidence: 97%

MAPK Kinase 3 Potentiates Chlamydia HSP60-Induced Inflammatory Response through Distinct Activation of NF-κB

Kang

Wang

Lü

et al. 2013

The Journal of Immunology

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“…A549 cells were infected with L. pneumophila with a multiplicity of infection (MOI) of 10 at 37uC and 5% CO 2 . GM-CSF ELISA A549 cells were infected as indicated, supernatants were collected and processed for GM-CSF-quantification by ELISA, according to manufacturer's instructions (BD Biosciences, Heidelberg, Germany) [11].…”

Section: Cell Linesmentioning

confidence: 99%

“…To clear L. pneumophila from the lung, a functionally intact innate immune system, particularly macrophages and polymorphonuclear leukocytes (PMNs), must be present [3,8]. Epithelial cells have been shown to liberate mediators such as granulocytemacrophage colony-stimulating factor (GM-CSF), interleukin-8, interferon (IFN)-b, and prostaglandin (PG)E 2 upon infection [4,5,[11][12][13][14]. GM-CSF is a 23-kDa haematopoietic growth factor that is able to stimulate in vitro survival, proliferation, differentiation and function of myeloid cells and their precursors, particularly PMNs, eosinophils, granulocytes, and monocytes/macrophages [15,16].…”

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confidence: 99%

PKC and PKC differentially regulate Legionella pneumophila-induced GM-CSF

Vardarova

Scharf²,

Lang³

et al. 2009

European Respiratory Journal

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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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“…Moreover, C. pneumoniae GroEL1 can activate the granulocyte-macrophage colony-stimulating factor in human bronchial epithelial cells almost as effectively as viable or UV-inactivated whole bacteria, giving rise to a sustained proinflammatory phenotype (43). Similarly, C. trachomatis GroEL1 induces endothelial cells, smooth muscle cells, and macrophages to produce adhesion factors and proinflammatory cytokines.…”

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confidence: 99%

Chlamydia pneumoniaeGroEL1 Protein Is Cell Surface Associated and Required for Infection of HEp-2 Cells

Wuppermann¹,

Mölleken

Julien

et al. 2008

J Bacteriol

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Chlamydia pneumoniae is an important obligate intracellular pathogen that replicates within an inclusion in the eukaryotic cell. The initial event of a chlamydial infection is the adherence to and subsequent uptake of the infectious elementary bodies (EBs) by the human cell. These processes require yet-unidentified bacterial and eukaryotic surface proteins. The GroEL1 protein, which exhibits a very strong antigenicity and in vitro can activate various eukaryotic cells, is a potential pathogenicity factor. We localized the protein during the infection process and found it in the inclusion but outside the chlamydial particles. GroEL1 was also localized on the surface of EBs, and the protein could be washed off the EBs. Latex beads coated with recombinantly produced GroEL1 (rGroEL1) bound in a dose-dependent manner to HEp-2 cells. Likewise, GroEL1, when expressed and displayed on the yeast cell surface, mediated adhesion to HEp-2 cells. Interestingly, the homologous GroEL2 and GroEL3 proteins showed no adhesive properties. Incubation of primary umbilical vein endothelial cells with soluble GroEL1 and GroEL1-coated latex beads activated the translocation of the general transcription factor NF-B into the nucleus. Finally, preincubation of HEp-2 cells with rGroEL1 significantly reduced subsequent infection with C. pneumoniae, although adhesion of infectious bacteria to eukaryotic cells was not affected. Taken together, these data support a role for extracellular GroEL1 in the establishment of the chlamydial infection.

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Mechanisms ofChlamydophila pneumoniae–Mediated GM-CSF Release in Human Bronchial Epithelial Cells

Cited by 29 publications

References 33 publications

MAPK Kinase 3 Potentiates Chlamydia HSP60-Induced Inflammatory Response through Distinct Activation of NF-κB

MAPK Kinase 3 Potentiates Chlamydia HSP60-Induced Inflammatory Response through Distinct Activation of NF-κB

PKC and PKC differentially regulate Legionella pneumophila-induced GM-CSF

Chlamydia pneumoniaeGroEL1 Protein Is Cell Surface Associated and Required for Infection of HEp-2 Cells

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