Glucocorticoids inhibit nontypeable Haemophilus influenzae-induced MUC5AC mucin expression via MAPK phosphatase-1-dependent inhibition of p38 MAPK

Komatsu, Kensei; Jono, Hirofumi; Lim, Jae Hyang; Imasato, Akira; Xu, Haidong; Kai, Hirofumi; Yan, Chen; Li, Jian Dong

doi:10.1016/j.bbrc.2008.10.091

Cited by 29 publications

(26 citation statements)

References 27 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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“…We also previously demonstrated that glucocorticoids inhibited p38 MAPK-mediated MUC5AC expression induced by NTHi via upregulation of MKP-1 gene expression (43). Because of the critical role of MAPKs, including ERK, in the regulation of innate immune and inflammatory responses, upregulation of MKP-1 could play an important role in tightly controlling overactive immune and inflammatory response in a negative-feedback manner.…”

Section: Discussionmentioning

confidence: 89%

Vinpocetine Inhibits Streptococcus pneumoniae–Induced Upregulation of Mucin MUC5AC Expression via Induction of MKP-1 Phosphatase in the Pathogenesis of Otitis Media

Lee

Komatsu

Lee

et al. 2015

The Journal of Immunology

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Mucin overproduction is a hallmark of otitis media (OM). Streptococcus pneumoniae is one of the most common bacterial pathogens causing OM. Mucin MUC5AC plays an important role in mucociliary clearance of bacterial pathogens. However, if uncontrolled, excessive mucus contributes significantly to conductive hearing loss. Currently, there is a lack of effective therapeutic agents that suppress mucus overproduction. In this study, we show that a currently existing antistroke drug, vinpocetine, a derivative of the alkaloid vincamine, inhibited S. pneumoniae–induced mucin MUC5AC upregulation in cultured middle ear epithelial cells and in the middle ear of mice. Moreover, vinpocetine inhibited MUC5AC upregulation by inhibiting the MAPK ERK pathway in an MKP-1–dependent manner. Importantly, ototopical administration of vinpocetine postinfection inhibited MUC5AC expression and middle ear inflammation induced by S. pneumoniae and reduced hearing loss and pneumococcal loads in a well-established mouse model of OM. Thus, these studies identified vinpocetine as a potential therapeutic agent for inhibiting mucus production in the pathogenesis of OM.

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“…Independently, dexamethasone attenuates NTHi-induced NF-kB activation, but also synergistically enhances NTHi-induced TLR2 expression via specific upregulation of MAPK phosphatase (MKP)-1 that, in turn, leads to dephosphorylation and inactivation of p38 MAPK. Glucocorticoid-mediated inhibition of NTHiinduced MUC5A expression also occurs via MKP-1-dependent inhibition of p38 MAPK [112][113][114][115].…”

Section: Impact Of Anti-inflammatory Therapies On Bacterial Respiratomentioning

confidence: 99%

Impact of cigarette smoke exposure on host-bacterial pathogen interactions

Garmendia¹,

Morey²,

Bengoechea³

2011

European Respiratory Journal

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The human respiratory tract of individuals with normal lung function maintains a finetuned balance, being asymptomatically colonised by the normal microbiota in the upper airways and sterile in the lower tract. This equilibrium may be disrupted by the exposure to insults such as cigarette smoke. In the respiratory tract, the complex and noxious nature of inhaled cigarette smoke alters host-microorganism interaction dynamics at all anatomical levels, causing infections in many cases. Moreover, continuous exposure to cigarette smoke itself causes deleterious effects on the host that can trigger the development of chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and lung cancer. COPD is an irreversible airflow obstruction associated with emphysema, fibrosis, mucus hypersecretion and persistent colonisation of the lower airways by opportunistic pathogens. COPD patients keep a stable (without exacerbation) but progressively worsening condition and suffer periodic exacerbations caused, in most cases, by infections. Although smoking and smoking-associated diseases are associated with a high risk of infection, most therapies aim to reduce inflammatory parameters, but do not necessarily take into account the presence of persistent colonisers. The effect of cigarette smoke on host-pathogen interaction dynamics in the respiratory tract, together with current and novel therapies, is discussed.

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Glucocorticoids inhibit nontypeable Haemophilus influenzae-induced MUC5AC mucin expression via MAPK phosphatase-1-dependent inhibition of p38 MAPK

Cited by 29 publications

References 27 publications

Antiinflammatory Role of MUC1 Mucin during Infection with NontypeableHaemophilus influenzae

Antiinflammatory Role of MUC1 Mucin during Infection with NontypeableHaemophilus influenzae

Vinpocetine Inhibits Streptococcus pneumoniae–Induced Upregulation of Mucin MUC5AC Expression via Induction of MKP-1 Phosphatase in the Pathogenesis of Otitis Media

Impact of cigarette smoke exposure on host-bacterial pathogen interactions

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