Differential regulation of<i>Moraxella catarrhalis</i>-induced interleukin-8 response by protein kinase C isoforms

Slevogt, Hortense; Maqami, L.; Vardarowa, K.; Beermann, Wiebke; Hocke, Andreas C.; Eitel, Julia; Schmeck, Bernd; Weimann, Andreas; Opitz, Bastian; Hippenstiel, Stefan; Suttorp, Norbert; N′Guessan, Philippe Dje

doi:10.1183/09031936.00103507

Cited by 18 publications

(13 citation statements)

References 48 publications

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“…Diverse microbial pathogens stimulate airway epithelial cells, leading to activation of the transcriptional activator NF-B and production of proinflammatory cytokines, such as IL-6 and IL-8 (5,15,20,28,30). In this study, we observed that CS inhibited IL-8 production brought about by NT H. influenzae and S. aureus in a dose-dependent manner.…”

Section: Discussionsupporting

confidence: 55%

Cigarette Smoke Inhibits Airway Epithelial Cell Innate Immune Responses to Bacteria

Rampersaud¹,

Aguilar²,

Randis³

et al. 2010

Infect Immun

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The human upper respiratory tract, including the nasopharynx, is colonized by a diverse array of microorganisms. While the host generally exists in harmony with the commensal microflora, under certain conditions, these organisms may cause local or systemic disease. Respiratory epithelial cells act as local sentinels of the innate immune system, responding to conserved microbial patterns through activation of signal transduction pathways and cytokine production. In addition to colonizing microbes, these cells may also be influenced by environmental agents, including cigarette smoke (CS). Because of the strong relationship among secondhand smoke exposure, bacterial infection, and sinusitis, we hypothesized that components in CS might alter epithelial cell innate immune responses to pathogenic bacteria. We examined the effect of CS condensate (CSC) or extract (CSE) on signal transduction and cytokine production in primary and immortalized epithelial cells of human or murine origin in response to nontypeable Haemophilus influenzae and Staphylococcus aureus. We observed that epithelial production of interleukin-8 (IL-8) and IL-6 in response to bacterial stimulation was significantly inhibited in the presence of CS (P < 0.001 for inhibition by either CSC or CSE). In contrast, epithelial production of beta interferon (IFN-␤) was not inhibited. CSC decreased NF-B activation (P < 0.05) and altered the kinetics of mitogen-activated protein kinase phosphorylation in cells exposed to bacteria. Treatment of CSC with antioxidants abrogated CSC-mediated reduction of epithelial IL-8 responses to bacteria (P > 0.05 compared to cells without CSC treatment). These results identify a novel oxidant-mediated immunosuppressive role for CS in epithelial cells.

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Section: Discussionsupporting

confidence: 55%

Cigarette Smoke Inhibits Airway Epithelial Cell Innate Immune Responses to Bacteria

Rampersaud¹,

Aguilar²,

Randis³

et al. 2010

Infect Immun

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“…In a previous study, PKCa has been shown to be important for COX-2 expression and subsequent PGE 2 release in L. pneumophila-infected alveolar epithelial cells [4]. Also, we demonstrated that Moraxella catarrhalis infection activates PKCa, e, and h which differentially regulate interleukin-8 gene transcription in human pulmonary epithelial cells [14]. Since the activation pattern of PKCs as well as their impact on inflammatory immune response depends on the pathogen implicated, the above described mechanism might be specific for a L. pneumophila.…”

Section: Discussionmentioning

confidence: 97%

“…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].…”

mentioning

confidence: 99%

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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“…The chromatin immunoprecipitation was performed as described previously (45). A549 cells were stimulated 1 h prior to fixation.…”

Section: Materials and Antibodiesmentioning

confidence: 99%

Dectin-1 Is Expressed in Human Lung and Mediates the Proinflammatory Immune Response to Nontypeable Haemophilus influenzae

et al. 2015

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The C-type lectin receptor Dectin-1 is expressed mainly on myeloid cells mediating the immune response targeting respiratory pathogens such as Aspergillus fumigatus and Mycobacterium tuberculosis. The pulmonary epithelium serves as an important interface for interactions between these pathogens and the respiratory tract. Therefore, we analyzed the expression pattern of Dectin-1 in the human lung. Immunohistochemically stained human lung sections from 17 out of 19 individuals were positive for Dectin-1, which was expressed mainly apically on bronchial and alveolar epithelium. Our results showed no correlation with chronic obstructive pulmonary disease (COPD) or the smoking habits of the patients. Nontypeable Haemophilus influenzae (NTHI), an important bacterial pathogen of the respiratory tract with significant importance in COPD, has also been proposed to be recognized by Dectin-1, suggesting a possible impact on the NTHI-dependent immune response in human airways. Therefore, the involvement of Dectin-1 in NTHI-triggered cytokine responses was investigated in primary normal human bronchial epithelial (NHBE) cells and in the A549 cell line stably transfected with Dectin-1. The presence of Dectin-1 significantly increased cytokine release in response to NTHI in NHBE and A549 cells. In addition, phosphorylation of the Dectin-1 hem-immunoreceptor tyrosine-based activation motif (hemITAM) was essential for the Dectin-1-triggered response to NTHI in A549 cells. In conclusion, in human airways, epithelium-expressed Dectin-1 may play a significant role in generating an NTHImediated, proinflammatory immune response. IMPORTANCEIn this study, we demonstrated, for the first time, the expression of Dectin-1 on human lung tissues and, in particular, pulmonary epithelium by making use of immunohistochemical staining. The epithelial lining of the human airways is an important interface for host-pathogen interactions. Therefore, our data suggest that epithelium-expressed Dectin-1 is of considerable importance for the interaction of the human airways with pathogens detected by this receptor, such as A. fumigatus and M. tuberculosis. Moreover, we further demonstrated that, in pulmonary epithelial cells, Dectin-1 enhances the proinflammatory immune response to NTHI. In COPD patients, NTHI is a major cause of respiratory tract infections and is associated with proinflammatory immune responses in the lower airways. Therefore, our data suggest that the functional interaction of Dectin-1 with NTHI in human airways may have an important impact on the pathogenesis of COPD.

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Differential regulation ofMoraxella catarrhalis-induced interleukin-8 response by protein kinase C isoforms

Cited by 18 publications

References 48 publications

Cigarette Smoke Inhibits Airway Epithelial Cell Innate Immune Responses to Bacteria

Cigarette Smoke Inhibits Airway Epithelial Cell Innate Immune Responses to Bacteria

PKCα and PKCϵ differentially regulateLegionella pneumophila-induced GM-CSF

Dectin-1 Is Expressed in Human Lung and Mediates the Proinflammatory Immune Response to Nontypeable Haemophilus influenzae

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