Endoplasmic Reticulum Stress Induces MUC5AC and MUC5B Expression in Human Nasal Airway Epithelial Cells
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Objectives. Endoplasmic reticulum (ER) stress is known to be associated with inflammatory airway diseases, and three major transmembrane receptors: double-stranded RNA-activated protein kinase-like ER kinase, inositol requiring enzyme 1, and activating transcription factor 6 (ATF6) play important roles in ER stress-related proinflammatory signaling. However, the effects of ER stress and these three major signaling pathways on the regulation of the production of airway mucins in human nasal airway epithelial cells have not been elucidated. Methods. In primary human nasal epithelial cells, the effect of tunicamycin (an ER stress inducer) and 4-phenylbutyric acid (4-PBA, ER stress inhibitor) on the expression of MUC5AC and MUC5B was investigated by reverse transcriptase-polymerase chain reaction, real-time polymerase chain reaction, enzyme immunoassay, and immunoblot analysis. Small interfering RNA (siRNA) transfection was used to identify the mechanisms involved. Results. Tunicamycin increased the expressions of MUC5AC and MUC5B and the mRNA expressions of ER stress-related signaling molecules, including spliced X-box binding protein 1 (XBP-1), transcription factor CCAAT-enhancer-binding protein homologous protein (CHOP), and ATF6. In addition, 4-PBA attenuated the tunicamycin-induced expressions of MUC5AC and MUC5B and the mRNA expressions of ER stress-related signaling molecules. Furthermore, siRNA knockdowns of XBP-1, CHOP, and ATF6 blocked the tunicamycin-induced mRNA expressions and glycoprotein productions of MUC5AC and MUC5B. Conclusion. These results demonstrate that ER stress plays an important role in the regulation of MUC5AC and MUC5B via the activations of XBP-1, CHOP, and ATF6 in human nasal airway epithelial cells.
Abstract
Objectives. Endoplasmic reticulum (ER) stress is known to be associated with inflammatory airway diseases, and three major transmembrane receptors: double-stranded RNA-activated protein kinase-like ER kinase, inositol requiring enzyme 1, and activating transcription factor 6 (ATF6) play important roles in ER stress-related proinflammatory signaling. However, the effects of ER stress and these three major signaling pathways on the regulation of the production of airway mucins in human nasal airway epithelial cells have not been elucidated. Methods. In primary human nasal epithelial cells, the effect of tunicamycin (an ER stress inducer) and 4-phenylbutyric acid (4-PBA, ER stress inhibitor) on the expression of MUC5AC and MUC5B was investigated by reverse transcriptase-polymerase chain reaction, real-time polymerase chain reaction, enzyme immunoassay, and immunoblot analysis. Small interfering RNA (siRNA) transfection was used to identify the mechanisms involved. Results. Tunicamycin increased the expressions of MUC5AC and MUC5B and the mRNA expressions of ER stress-related signaling molecules, including spliced X-box binding protein 1 (XBP-1), transcription factor CCAAT-enhancer-binding protein homologous protein (CHOP), and ATF6. In addition, 4-PBA attenuated the tunicamycin-induced expressions of MUC5AC and MUC5B and the mRNA expressions of ER stress-related signaling molecules. Furthermore, siRNA knockdowns of XBP-1, CHOP, and ATF6 blocked the tunicamycin-induced mRNA expressions and glycoprotein productions of MUC5AC and MUC5B. Conclusion. These results demonstrate that ER stress plays an important role in the regulation of MUC5AC and MUC5B via the activations of XBP-1, CHOP, and ATF6 in human nasal airway epithelial cells.
참고문헌 (24)
- Cao SS, "Endoplasmic reticulum stress interacts with inflammation in human diseases", J Cell Physiol, 231(2), pp.288~294 (2016)
- Hasnain SZ, "The interplay between endoplasmic reticulum stress and inflammation", Immunol Cell Biol, 90(3), pp.260~270 (2012)
- 김소리, "Endoplasmic Reticulum Stress and the Related Signaling Networks in Severe Asthma", Allergy, Asthma & Immunology Research, 7(2), pp.106~117 (2015), 대한천식알레르기학회
- Wei J, "Protein misfolding and endoplasmic reticulum stress in chronic lung disease", Chest, 143(4), pp.1098~1105 (2013)
- Martino MB, "The ER stress transducer IRE1β is required for airway epithelial mucin production", Mucosal Immunol, 6(3), pp.639~654 (2013)
- Mijosek V, "Endoplasmic reticulum stress is a danger signal promoting innate inflammatory responses in bronchial epithelial cells", J Innate Immun, 8(5), pp.464~478 (2016)
- Delmotte P, "Interaction between endoplasmic", sarcoplasmic reticulum stress(ER, Can J Physiol Pharmacol, pp.2015, 93(2)[DOI]
- Ali MS, "Upper airway mucin gene expression : a review", Laryngoscope, 117(5), pp.932~938 (2007)
- Rose MC, "Respiratory tract mucin genes and mucin glycoproteins in health and disease", Physiol Rev, 86(1), pp.245~278 (2006)
- Roy MG, "Muc5b is required for airway defence", Nature, 505(7483), pp.412~416 (2014)
- Ha EV, "Novel therapies to inhibit mucus synthesis and secretion in airway hypersecretory diseases", Pharmacology, 97(1-2), pp.84~100 (2016)
- Voynow JA, "Mucins, mucus, and sputum", Chest, 135(2), pp.505~512 (2009)
- Song SY, "Expression of leptin receptor in nasal polyps : leptin as a mucosecretagogue", Laryngoscope, 120(5), pp.1046~1050 (2010)
- Kim YD, "Effect of beta-glucan on MUC4and MUC5B expression in human airway epithelial cells", Int Forum Allergy Rhinol, 5(8), pp.708~715 (2015)
- Ron D, "Signal integration in the endoplasmic reticulum unfolded protein response", Nat Rev Mol Cell Biol, 8(7), pp.519~529 (2007)
- Oyadomari S, "Roles of CHOP", GADD153 in endoplasmic reticulum stress, 2004, pp.11(4), 381~389
- Garg AD, "ER stress-induced inflammation: does it aid or impede disease progression?", Trends Mol Med, 18(10), pp.589~598 (2012)
- Jorgensen E, "Cigarette smoke induces ndoplasmic reticulum stress and the unfolded protein response in normal and malignant human lung cells", BMC Cancer, 8, pp.229~ (2008)
- Kim SR, "Endoplasmic reticulum stress influences bronchial asthma pathogenesis by modulating nuclear factor kappaB activation", J Allergy Clin Immunol, 132(6), pp.1397~1408 (2013)
- Martino ME, "Airway epithelial inflammation-induced endoplasmic reticulum Ca2+ store expansion is mediated by X-box binding protein-1", J Biol Chem, 284(22), pp.14904~14913 (2009)
- Kim YM, "Staphylococcus aureus enterotoxin B-induced endoplasmic reticulum stress response is associated with chronic rhinosinusitis with nasal polyposis", Clin Biochem, 47(1-2), pp.96~103 (2014)
- Schroeder BW, "AGR2 is induced in asthma and promotes allergen-induced mucin overproduction", Am J Respir Cell Mol Biol, 47(2), pp.178~185 (2012)
- Kirkham S, "Heterogeneity of airways mucus: variations in the amounts and glycoforms of the major oligomeric mucins MUC5AC and MUC5B", Biochem J, 361(Pt 3), pp.537~546 (2002)
- Morcillo EJ, "Mucus and MUC in asthma", Curr Opin Pulm Med, 12(1), pp.1~6 (2006)