TNF-α induces<i>MUC1</i>gene transcription in lung epithelial cells: its signaling pathway and biological implication

Koga, Takeshi; Kuwahara, Ippei; Lillehoj, Erik P.; Lu, Wenju; Miyata, Takeshi; Isohama, Yoichiro; Kim, K. Chul

doi:10.1152/ajplung.00491.2006

Cited by 63 publications

(85 citation statements)

References 45 publications

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“…TNF-a stimulates the expression of MUC1 in A549 cells (39,40), human uterine epithelial cells (41), and human prostate cells (42). The molecular mechanism of the TNF-a-induced up-regulation of MUC1 was described elsewhere (39).…”

Section: Discussionmentioning

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: Discussionmentioning

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 overexpression in airway epithelial cells under pulmonary bacterial infection was considered as an immune response which in turn inhibits excessive inflammation and could be controlled by proinflammatory cytokine like TNF-α (9,19,20). AECOPD is mainly caused by bacterial infection in the airway and lung.…”

Section: Discussionmentioning

confidence: 99%

Sputum mucin 1 is increased during the acute phase of chronic obstructive pulmonary disease exacerbation

Zheng¹,

Qi²,

Xu³

et al. 2017

J. Thorac. Dis.

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Background: Mucin 1 (MUC1) is a membrane tethered protein on airway epithelial cells. This protein is upregulated and plays an important anti-inflammatory role during acute lung inflammation. However, the relationship between sputum MUC1 level and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is unknown. Methods:The levels of MUC1, IL-8, and TNF-α in induced sputum from 78 COPD patients were assessed by ELISA. The association between COPD exacerbation and MUC1 fragment levels was analyzed.An acute airway inflammation mouse model was established by intranasal LPS inhalation. The expression of Muc1 in lung and the levels of Muc1, TNF-α and KC in BAL fluid from mice were determined with western blotting and ELISA, respectively.Results: Higher levels of MUC1 membrane-tethered (CT) and extracellular (EC) fragments, cytokines TNF-α and IL-8, more leucocyte and neutrophil counts were found in sputum from COPD patients in acute than in remission phase. Linear regression analysis confirmed that the level of sputum MUC1 CT fragment is positively correlated with sputum neutrophil number and patients' age; whereas the sputum EC fragment level is correlated inversely with FEV1/FVC value and positively with patients' age. Inhalation of lipopolysaccharide (LPS) induced acute lung inflammation in mice which exhibited increased levels of Muc1 CT fragment in lung and only Muc1 EC fragment increase in BAL fluid.Conclusions: Unlike pure bacterial induced lung inflammation, both sputum MUC1 CT and EC fragments are increased during acute exacerbation of COPD. The clinical benefits from measuring the changes of various sputum MUC1 fragments in AECOPD need to be elucidated in future studies.

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“…TNFR1 is also important for the clearance of P. aeruginosa (191). TNFR1 also regulates expression of MUC1, which is an important antiinflammatory component and binding site for P. aeruginosa on airway epithelial cells (47,52,63,192).…”

Section: Tnfr1mentioning

confidence: 99%

Innate Immunity in the Respiratory Epithelium

Parker

Prince

2011

Am J Respir Cell Mol Biol

393

404

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The airway epithelium represents the first point of contact for inhaled foreign organisms. The protective arsenal of the airway epithelium is provided in the form of physical barriers and a vast array of receptors and antimicrobial compounds that constitute the innate immune system. Many of the known innate immune receptors, including the Toll-like receptors and nucleotide oligomerization domain-like receptors, are expressed by the airway epithelium, which leads to the production of proinflammatory cytokines and chemokines that affect microorganisms directly and recruit immune cells, such as neutrophils and T cells, to the site of infection. The airway epithelium also produces a number of resident antimicrobial proteins, such as lysozyme, lactoferrin, and mucins, as well as a swathe of cationic proteins. Dysregulation of the airway epithelial innate immune system is associated with a number of medical conditions that can result in compromised immunity and chronic inflammation of the lung. This review focuses on the innate immune capabilities of the airway epithelium and its role in protecting the lung from infection as well as the outcomes when its function is compromised.

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TNF-α inducesMUC1gene transcription in lung epithelial cells: its signaling pathway and biological implication

Cited by 63 publications

References 45 publications

Antiinflammatory Role of MUC1 Mucin during Infection with NontypeableHaemophilus influenzae

Antiinflammatory Role of MUC1 Mucin during Infection with NontypeableHaemophilus influenzae

Sputum mucin 1 is increased during the acute phase of chronic obstructive pulmonary disease exacerbation

Innate Immunity in the Respiratory Epithelium

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