Nontypeable Haemophilus influenzae induces COX-2 and PGE2 expression in lung epithelial cells via activation of p38 MAPK and NF-kappa B

Xu, Feng; Xu, Zhihao; Zhang, Rong; Wu, Zhiwei; Lim, Jae Hyang; Koga, Tomoaki; Li, Jian Dong; Shen, Huahao

doi:10.1186/1465-9921-9-16

Cited by 44 publications

(30 citation statements)

References 30 publications

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“…Multiple studies demonstrated the utility of NTHi lysate in elucidating the pathogenesis and host response to bacterial infection (6,15,(17)(18)(19)(20)(21)(22)(23). Therefore, we initially determined whether NTHi lysate induces an in vitro inflammatory response in A549 cells, a human lung epithelial cell line that is commonly used to study airway inflammation.…”

Section: Nthi Lysate Increases the Release Of Il-8 And Cellular Concementioning

confidence: 99%

Antiinflammatory Role of MUC1 Mucin during Infection with NontypeableHaemophilus influenzae

Kyo

Kato

Park

et al. 2012

Am J Respir Cell Mol Biol

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MUC1 (or Muc1 in nonhuman species) is a membrane-tethered mucin expressed on the apical surface of mucosal epithelia (including those of the airways) that suppresses Toll-like receptor (TLR) signaling. We sought to determine whether the anti-inflammatory effect of MUC1 is operative during infection with nontypeable Haemophilus influenzae (NTHi), and if so, which TLR pathway was affected. Our results showed that: (1) a lysate of NTHi increased the early release of IL-8 and later production of MUC1 protein by A549 cells in dose-dependent and time-dependent manners, compared with vehicle control; (2) both effects were attenuated after transfection of the cells with a TLR2-targeting small interfering (si) RNA, compared with a control siRNA; (3) the NTHi-induced release of IL-8 was suppressed by an overexpression of MUC1, and was enhanced by the knockdown of MUC1; (4) the TNF-a released after treatment with NTHi was sufficient to up-regulate MUC1, which was completely inhibited by pretreatment with a soluble TNF-a receptor; and (5) primary murine tracheal surface epithelial (MTSE) cells from Muc1 knockout mice exhibited an increased in vitro production of NTHi-stimulated keratinocyte chemoattractant compared with MTSE cells from Muc1-expressing animals. These results suggest a hypothetical feedback loop model whereby NTHi activates TLRs (mainly TLR2) in airway epithelial cells, leading to the increased production of TNF-a and IL-8, which subsequently up-regulate the expression of MUC1, resulting in suppressed TLR signaling and decreased production of IL-8. This report is the first, to the best of our knowledge, demonstrating that the inflammatory response in airway epithelial cells during infection with NTHi is controlled by MUC1 mucin, mainly through the suppression of TLR2 signaling.

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Section: Nthi Lysate Increases the Release Of Il-8 And Cellular Concementioning

confidence: 99%

Antiinflammatory Role of MUC1 Mucin during Infection with NontypeableHaemophilus influenzae

Kyo

Kato

Park

et al. 2012

Am J Respir Cell Mol Biol

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“…Activation of toll-like receptors may similarly stimulate the formation of PGE 2 [45][46][47]. Hitherto an effect of Pam3CSK4 on prostaglandin formation has, however, not been shown.…”

Section: Discussionmentioning

confidence: 99%

Lipopeptides in the Triggering of Erythrocyte Cell Membrane Scrambling

Wang

Mahmud²,

Föller³

et al. 2008

Cell Physiol Biochem

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Sepsis is paralleled by anemia, an effect partially resulting from eryptosis, the suicidal death of erythrocytes. Eryptosis is characterized by cell membrane scrambling with phosphatidylserine exposure at the erythrocyte surface. Pathogen-induced eryptosis may partially result from interaction of bacterial cell wall components such as lipoproteins with the erythrocyte cell membrane. The present study explored, whether the synthetic lipopeptide Pam3CSK4 mimicking the acylated amino terminus of bacterial lipoproteins triggers eryptosis. According to annexin-V-binding in FACS analysis, Pam3CSK4 (1 µg/ml) stimulated phosphatidylserine exposure, an effect significantly blunted in the nominal absence of Ca 2+ . According to Fluo3 fluorescence, Pam3CSK4 increased cytosolic Ca 2+ activity and moderately stimulated erythrocytic ceramide formation, both major triggers of eryptosis. In conclusion, bacterial lipoproteins participate in the stimulation of erythrocyte cell membrane scrambling by bacterial cell wall components. Thus, lipoproteindependent suicidal erythrocyte death may contribute to the pleotropic effects of sepsis.

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“…p38 MAPK regulates PGE 2 synthesis in nonmacrophage cells, including lung epithelial cells infected with Haemophilus influenzae (18). F. tularensis stimulates the phosphorylation and activation of p38 MAPK following infection of macrophages (19).…”

Section: Resultsmentioning

confidence: 99%

Janus Kinase 3 Activity Is Necessary for Phosphorylation of Cytosolic Phospholipase A2 and Prostaglandin E2 Synthesis by Macrophages Infected with Francisella tularensis Live Vaccine Strain

et al. 2014

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Francisella tularensis, the causative agent of tularemia, modulates the host immune response to gain a survival advantage within the host. One mechanism of immune evasion is the ability of F. tularensis to induce the synthesis of the small lipid mediator prostaglandin E2 (PGE 2 ), which alters the host T cell response making the host more susceptible to Francisella growth. PGE 2 is synthesized by a tightly regulated biosynthetic pathway following stimulation. The synthesis of PGE 2 begins with the liberation of arachidonic acid (AA) from membrane phospholipids by cytosolic phospholipase A2 (cPLA 2 ). AA is subsequently converted to the unstable intermediate PGH 2 by cyclooxygenase-2 (COX-2), and PGH 2 undergoes an isomerization reaction to generate PGE 2 . Our objective was to identify F. tularensis-activated host signaling pathways that regulate the activity of the enzymes in the PGE 2 -biosynthetic pathway. In this study, we show that cPLA 2 , p38 mitogen-activated protein kinase (MAPK), and Janus kinase 3 (JAK3) signaling are necessary for F. tularensis-induced PGE 2 production. Inhibition of JAK3 activity reduced the phosphorylation of cPLA 2 and COX-2 protein levels. In addition, JAK3 regulates cPLA 2 phosphorylation independent of transcription. Moreover, p38 MAPK activity is required for F. tularensis-induced COX-2 protein synthesis, but not for the phosphorylation of cPLA 2 . This research highlights a unique signaling axis in which JAK3 and p38 MAPK regulate the activity of multiple enzymes of the PGE 2 -biosynthetic pathway in macrophages infected with F. tularensis.

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Nontypeable Haemophilus influenzae induces COX-2 and PGE2 expression in lung epithelial cells via activation of p38 MAPK and NF-kappa B

Cited by 44 publications

References 30 publications

Antiinflammatory Role of MUC1 Mucin during Infection with NontypeableHaemophilus influenzae

Antiinflammatory Role of MUC1 Mucin during Infection with NontypeableHaemophilus influenzae

Lipopeptides in the Triggering of Erythrocyte Cell Membrane Scrambling

Janus Kinase 3 Activity Is Necessary for Phosphorylation of Cytosolic Phospholipase A2 and Prostaglandin E2 Synthesis by Macrophages Infected with Francisella tularensis Live Vaccine Strain

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