Mesenchymal Stem Cells Require MARCKS Protein for Directed Chemotaxis <i>In Vitro</i>

Miller, Jeffrey D.; Lankford, Susan M.; Adler, Kenneth B.; Brody, Arnold R.

doi:10.1165/rcmb.2010-0015rc

Cited by 23 publications

(18 citation statements)

References 36 publications

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“…The results of the secretion studies supported the potential anti-inflammatory role of miR-21 in airway epithelium, as treatment with the miR-21 inhibitor, which increases MARCKS expression, also provoked secretion of mucin by cells treated with LPS, while treatment with the miR-21 mimic, which downregulates MARCKS expression, resulted in decreased mucin secretion. To ascertain that indeed MARCKS was functionally associated with the secretory responses, pretreatment of the cells with the MANS peptide, a reagent that is identical to the evolutionarily-conserved N-terminus of MARCKS and which has been shown to inhibit mucin secretion and other functions of MARCKS [3, 6,[31][32][33][34], reduced secretion in cells treated with the either the control HiPerFect transfection reagent, cells transfected with the miR-21 inhibitor, or cells treated with the miR-21 mimic/activator.…”

Section: Discussionmentioning

confidence: 99%

Mir-21 Regulation of MARCKS Protein and Mucin Secretion in Airway Epithelial Cells

Lampe¹,

Fang²,

Yin³

et al. 2013

OJRD

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Hypersecretion of mucus characterizes many inflammatory airway diseases, including asthma, chronic bronchitis, and cystic fibrosis. Excess mucus causes airway obstruction, reduces pulmonary function, and can lead to increased morbidity and mortality. MicroRNAs are small non-coding pieces of RNA which regulate other genes by binding to a complementary sequence in the target mRNA. The microRNA miR-21 is upregulated in many inflammatory conditions and, interestingly, miR-21 has been shown to target the mRNA of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS), a protein that is an important regulator of airway mucin (the solid component of mucus) secretion. In these studies, we determined that exposure of primary, well-differentiated, normal human bronchial epithelial (NHBE) cells to the pro-inflammatory stimulus lipopolysaccharide (LPS) increased expression of both miR-21 and MARCKS in a time-dependent manner. To investigate whether miR-21 regulation of MARCKS played a role in mucin secretion, two separate airway epithelial cell lines, HBE1 (papilloma virus transformed) and NCI-H292 (mucodepidermoid derived) were utilized, since manipulation of miR-21 is performed via transfection of commercially-available miR-21 inhibitors and mimics/activators. Treatment of HBE1 cells with LPS caused concentration-dependent increases in expression of both miR-21 and MARCKS mRNA and protein. The miR-21 inhibitor effectively reduced levels of miR-21 in the cells, coincident with an increase in MARCKS mRNA expression over time as well as enhanced mucin secretion, while the miR-21 mimic/activator increased levels of miR-21, which coincided with a decrease in expression of MARCKS and a decrease in mucin secretion. These results suggest that miR-21 is increased in airway epithelial cells following exposure to LPS, and that miR-21 downregulates expression of MARCKS, which may decrease mucin secretion by the cells. Thus, miR-21 may act as a negative feedback regulator of mucin secretion in airway epithelial cells, and may do so, at least in part, by downregulating expression of MARCKS.

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Section: Discussionmentioning

confidence: 99%

Mir-21 Regulation of MARCKS Protein and Mucin Secretion in Airway Epithelial Cells

Lampe¹,

Fang²,

Yin³

et al. 2013

OJRD

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“…It has been shown to have major roles in, for example: secretion, including airway mucin secretion [3-11], cellular migration [20-24] brain development [25], cell adhesion [14], phagocytosis [26], and cell cycle regulation [27]. While precise mechanisms for these diverse functions remain unkown, MARCKS is known to interact with cytoskeletal components and can bind and crosslink actin filaments within cells [28].…”

Section: Discussionmentioning

confidence: 99%

Calpain and MARCKS protein regulation of airway mucin secretion

Lampe

Park

Fang

et al. 2012

Pulmonary Pharmacology & Therapeutics

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“…In previous studies, we have shown that a key molecule regulating directed in vitro migration of neutrophils (4-7) and other inflammatory cells (8,9) is myristoylated alanine-rich C kinase substrate (MARCKS) protein. These reports used a peptide that inhibits MARCKS function called the myristoylated N-terminal sequence (MANS) peptide (10).…”

Section: Clinical Relevancementioning

confidence: 99%

An Inhaled Inhibitor of Myristoylated Alanine-Rich C Kinase Substrate Reverses LPS-Induced Acute Lung Injury in Mice

Yin

Fang

Park³

et al. 2016

Am J Respir Cell Mol Biol

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Intratracheal instillation of bacterial LPS is a well-established model of acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS). Because the myristoylated alanine-rich C kinase substrate (MARCKS) protein is involved in neutrophil migration and proinflammatory cytokine production, we examined whether an aerosolized peptide that inhibits MARCKS function could attenuate LPS-induced lung injury in mice. The peptide, BIO-11006, was delivered at 50 mM via inhalation either just before intratracheal instillation of 5 mg of LPS into Balb/C mice, or 4, 12, 24, or 36 hours after LPS instillation. Effects of BIO-11006 were evaluated via analysis of mouse disease-related behavior, lung histology, bronchoalveolar lavage fluid total protein, neutrophil counts and percentages, cytokine (KC [CXCl1, mouse IL-8 equivalent] and TNF-a) expression, and activation of NF-kB in lung tissue. Treatment with aerosolized BIO-11006 at 0, 4, 12, 24, and even 36 hours after LPS instillation reversed the disease process: mouse behavior returned to normal after two treatments 12 hours apart with the inhaled peptide after LPS injury, whereas control LPS-instilled animals treated with PBS only remained moribund. Histological appearance of inflammation, bronchoalveolar lavage fluid protein levels, leukocyte and neutrophil numbers, KC and TNF-a gene and protein expression, and NF-kB activation were all significantly attenuated by inhaled BIO-11006 at all time points. These results implicate MARCKS protein in the pathogenesis of ALI/ARDS and suggest that MARCKS-inhibitory peptide(s), delivered by inhalation, could represent a new and potent therapeutic treatment for ALI/ARDS, even if administered well after the disease process has begun.Keywords: myristoylated alanine-rich C kinase substrate; acute lung injury; LPS; neutrophils Clinical RelevanceThese studies show that treatment of mice with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) with an inhaled inhibitor of myristoylated alanine-rich C kinase substrate (MARCKS) protein reverses disease progression, even when treatment is initiated well into the disease process, a time when the animals are moribund. These results implicate MARCKS protein in the pathogenesis of ALI/ARDS and suggest that MARCKS-inhibitory peptide(s), delivered by inhalation, could represent a new and potent therapeutic treatment for ALI/ARDS, even if administered well after the disease process has begun. Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are major causes of respiratory failure; worldwide, over 1 million cases occur annually, with over 200,000 adult and 20,000 pediatric cases per year in the United States. This disorder is characterized by a large influx of leukocytes, especially neutrophils, to the lung as part of an acute inflammatory response, with injury to epithelial and endothelial cell barriers and pulmonary edema, all of which lead to respiratory failure. Treatment options remain limited to mechanical ventilation...

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Mesenchymal Stem Cells Require MARCKS Protein for Directed Chemotaxis In Vitro

Cited by 23 publications

References 36 publications

Mir-21 Regulation of MARCKS Protein and Mucin Secretion in Airway Epithelial Cells

Mir-21 Regulation of MARCKS Protein and Mucin Secretion in Airway Epithelial Cells

Calpain and MARCKS protein regulation of airway mucin secretion

An Inhaled Inhibitor of Myristoylated Alanine-Rich C Kinase Substrate Reverses LPS-Induced Acute Lung Injury in Mice

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