Deletion of the mucin-like molecule muc1 enhances dendritic cell activation in response to toll-like receptor ligands.
ABSTRACT Dendritic cells (DC) are potent professional antigen-presenting cells that drive primary immune responses to infections or other agonists perceived as 'dangerous'. Muc1 is the only cell surface mucin or MUC gene product that is expressed in DC. Unlike other members of this glycoprotein family, Muc1 possesses a unique cytosolic region capable of signal transduction and attenuating toll-like receptor (TLR) activation. The expression and function of Muc1 has been intensively investigated on epithelial and tumor cells, but relatively little is known about its function on DC. We hypothesized that Muc1 would influence in vitro generation and primary DC activation in response to the TLR4 and TLR5 ligands lipopolysaccharide and flagellin. Compared with Muc1(+/+) DC, we found that Muc1(-/-) DC were constitutively activated, as determined by higher expression of co-stimulatory molecules (CD40, CD80 and CD86), greater secretion of immunoregulatory cytokines (TNF-alpha and VEGF), and better stimulation of allogeneic naïve CD4+ T cell proliferation. After activation by either LPS or flagellin and co-culture with allogeneic CD4+ T cells, Muc1(-/-) DC also induced greater secretion of TNF-alpha and IFN-gamma compared to similarly activated Muc1(+/+) DC. Taken together, our results indicate that deletion of Muc1 promotes a heightened functional response of DC in response to TLR4 and TLR5 signaling pathways, and suggests a previously under-appreciated role for Muc1 in regulating innate immune responses of DC.
- Journal of Innate Immunity - J INNATE IMMUN. 01/2011; 3:109-110.
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ABSTRACT: Mucus clearance is the first defense of a normal airway against airborne pathogens and pollutants. However, mucus hypersecretion—an important feature of chronic obstructive pulmonary disease (COPD), especially the chronic bronchitis phenotype—contributes to disease pathology and mortality. Prescriptions of some mucoactive medications, e.g. N-acetylcysteine and carbocysteine, have proved beneficial for COPD management. Mucins are large-molecular-weight glycoproteins which constitute the major solid components of mucus, giving mucus its viscous and elastic properties and enabling its defensive function. Most-expressed in the airway are three membrane-tethered mucins (MUC1, MUC4, and MUC16) and three gel-forming secreted mucins (MUC2, MUC5AC, and MUC5B). Although over-expression of all these mucins has been observed or postulated in COPD lungs, none has been specifically evaluated as affecting COPD. Evidence regarding immunosuppressive, bacterial-adhesive, anti-inflammatory, and tumorigenic effects of MUC1 in other disease conditions suggests MUC1 may contribute to immune suppression, airway remodeling, mucus obstruction, bacterial colonization, and disruption of epithelium integrity in COPD. Regulation of mucin synthesis and secretion is increasingly well understood. Mucin over-expression in COPD is probably caused by a combination of microbial products, airborne pollutants, and mediators of inflammation. Further studies are needed to determine the individual function and regulatory signaling of each mucin in COPD airways, with the objectives of better understanding the disease mechanism and of developing novel therapeutics for COPD treatment.Current Respiratory Care Reports. 09/2013; 2(3).
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ABSTRACT: Airway mucus constitutes a thin layer of airway surface liquid with component macromolecules that covers the luminal surface of the respiratory tract. The major function of mucus is to protect the lungs through mucociliary clearance of inhaled foreign particles and noxious chemicals. Mucus is comprised of water, ions, mucin glycoproteins, and a variety of other macromolecules, some of which possess anti-microbial, anti-protease, and anti-oxidant activities. Mucins comprise the major protein component of mucus and exist as secreted and cell-associated glycoproteins. Secreted, gel-forming mucins are mainly responsible for the viscoelastic property of mucus, which is crucial for effective mucociliary clearance. Cell-associated mucins shield the epithelial surface from pathogens through their extracellular domains and regulate intracellular signaling through their cytoplasmic regions. However, neither the exact structures of mucin glycoproteins, nor the manner through which their expression is regulated, are completely understood. This chapter reviews what is currently known about the cellular and molecular properties of airway mucins.International review of cell and molecular biology 01/2013; 303:139-202. · 4.52 Impact Factor