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Silencing of MUC8 by siRNA increases P2Y₂-induced airway inflammation.
- Source :
-
American journal of physiology. Lung cellular and molecular physiology [Am J Physiol Lung Cell Mol Physiol] 2015 Mar 15; Vol. 308 (6), pp. L495-502. Date of Electronic Publication: 2015 Jan 09. - Publication Year :
- 2015
-
Abstract
- Mucin hypersecretion and overproduction are frequent manifestations of respiratory disease. Determining the physiological function of airway mucin is presently considered more important than identifying the relevant signaling pathways. The lack of a full-length human mucin 8 (MUC8) cDNA sequence has hindered the generation of a Muc8 knockout mouse line. Thus, the precise physiological functions of MUC8 are unclear. Herein, we investigated the function of MUC8 using a small-interfering RNA (siRNA)-mediated genetic silencing approach in human airway epithelial cells. Herein, intracellular IL-1α production was stimulated by an ATP/P2Y2 complex. While ATP/P2Y₂ increased IL-1α secretion in a time-dependent manner, treatment with P2Y₂-specific siRNA significantly decreased IL-1α secretion. Moreover, ATP increased P2Y₂-mediated upregulation of MUC8 expression; however, IL-1α significantly decreased the extent to which ATP/P2Y₂ upregulated MUC8 expression. Interestingly, treatment with MUC8-specific siRNA decreased the production of anti-inflammatory cytokines (TGF-β and IL-1 receptor antagonist) and increased the production of inflammatory cytokines (IL-1α and IL-6) in our system. In addition, siRNA-mediated knockdown of MUC8 expression dramatically increased the secretion of inflammatory chemokines and resulted in an approximately threefold decrease in cell chemotaxis. We propose that MUC8 may function as an anti-inflammatory mucin that participates in inflammatory response by attracting immune cells/cytokines to the site of inflammation. Our results provide new insight into the physiological function of MUC8 and enhance our understanding of mucin overproduction during airway inflammation.<br /> (Copyright © 2015 the American Physiological Society.)
- Subjects :
- Animals
Cell Line, Tumor
Humans
Inflammation genetics
Inflammation metabolism
Inflammation pathology
Interleukin 1 Receptor Antagonist Protein genetics
Interleukin 1 Receptor Antagonist Protein metabolism
Interleukin-1alpha genetics
Interleukin-1alpha metabolism
Interleukin-6 genetics
Interleukin-6 metabolism
Mice
Mice, Knockout
Mucins genetics
Receptors, Purinergic P2Y2 genetics
Respiratory Tract Diseases genetics
Respiratory Tract Diseases pathology
Transforming Growth Factor beta genetics
Transforming Growth Factor beta metabolism
Adenosine Triphosphate metabolism
Gene Silencing
Mucins biosynthesis
RNA, Small Interfering
Receptors, Purinergic P2Y2 metabolism
Respiratory Tract Diseases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1504
- Volume :
- 308
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Lung cellular and molecular physiology
- Publication Type :
- Academic Journal
- Accession number :
- 25575516
- Full Text :
- https://doi.org/10.1152/ajplung.00332.2014