A Primate-Specific RNA-Binding Protein (RBMXL3) Is Involved in Glucocorticoid Regulation of Human Pulmonary Surfactant Protein B (SP-B) mRNA Stability

2021 ◽  
Author(s):  
Lidan Liu ◽  
Xiangli Liu ◽  
Weizhen Bi ◽  
Joseph L Alcorn
Keyword(s):  
Epithelial Cells ◽  
Mrna Stability ◽  
Pulmonary Surfactant ◽  
Rna Binding ◽  
Surfactant Protein ◽  
Lung Epithelial Cells ◽  
Mouse Lung ◽  
Surfactant Protein B ◽  
Lung Epithelial ◽  
Protein B

The ability of pulmonary surfactant to reduce alveolar surface tension requires adequate levels of surfactant protein B (SP-B). Dexamethasone (DEX) increases human SP-B expression, in part, through increased SP-B mRNA stability. A 30 nt-long hairpin element (RBE) in the 3'-untranslated region of human SP-B mRNA mediates both DEX-induced and intrinsic mRNA stability, but the mechanism is unknown. Proteomic analysis of RBE-interacting proteins identified a primate-specific protein; RNA binding motif X-linked-like-3 (RBMXL3). siRNA directed against RBMXL3 reduces DEX-induced SP-B mRNA expression in human bronchoalveolar cells. Human SP-B mRNA stability, measured by our dual cistronic plasmid assay, is unaffected by DEX in mouse lung epithelial cells lacking RBMXL3, but DEX increases human SP-B mRNA stability when RBMXL3 is expressed and requires the RBE. In the absence of DEX, RBE interacts with cellular proteins, reducing intrinsic SP-B mRNA stability in human and mouse lung epithelial cells. RBMXL3 specifically binds the RBE in vitro while RNA immunoprecipitation and affinity chromatography analyses indicate that binding is enhanced in the presence of DEX. These results describe a model where intrinsic stability of human SP-B mRNA is reduced through binding of cellular mRNA decay factors to RBE, which is then relieved through DEX-enhanced binding of primate-specific RBMXL3.

scholarly journals LPS-Treated Macrophage Cytokines Repress Surfactant Protein–B in Lung Epithelial Cells

2013 ◽  
Vol 49 (2) ◽  
pp. 306-315 ◽  
Author(s):  
Kiflai Bein ◽  
Michelangelo Di Giuseppe ◽  
Steven E. Mischler ◽  
Luis A. Ortiz ◽  
George D. Leikauf
Keyword(s):  
Epithelial Cells ◽  
Surfactant Protein ◽  
Lung Epithelial Cells ◽  
Surfactant Protein B ◽  
Lung Epithelial ◽  
Protein B

scholarly journals Expression of surfactant protein B is dependent on cell density in H441 lung epithelial cells

PLoS ONE ◽  
2017 ◽  
Vol 12 (9) ◽  
pp. e0184556 ◽  
Author(s):  
Markus Fehrholz ◽  
Silvia Seidenspinner ◽  
Steffen Kunzmann
Keyword(s):  
Epithelial Cells ◽  
Cell Density ◽  
Surfactant Protein ◽  
Lung Epithelial Cells ◽  
Surfactant Protein B ◽  
Lung Epithelial ◽  
Protein B

scholarly journals Sequences of a hairpin structure in the 3′-untranslated region mediate regulation of human pulmonary surfactant protein B mRNA stability

2012 ◽  
Vol 302 (10) ◽  
pp. L1107-L1117 ◽  
Author(s):  
Helen W. Huang ◽  
David E. Payne ◽  
Weizhen Bi ◽  
Su Pan ◽  
Shirley R. Bruce ◽  
...  
Keyword(s):  
Mrna Stability ◽  
Hormonal Regulation ◽  
Untranslated Region ◽  
Pulmonary Surfactant ◽  
Specific Binding ◽  
Surfactant Protein ◽  
Hairpin Structure ◽  
Cytosolic Proteins ◽  
Surfactant Protein B ◽  
Protein B

The ability of pulmonary surfactant to reduce alveolar surface tension requires adequate expression of surfactant protein B (SP-B). Dexamethasone (DEX, 10−7 M) increases human SP-B mRNA stability by a mechanism that requires a 126-nt-long segment (the 7.6S region) of the 3′-untranslated region (3′-UTR). The objective of this study was to identify sequences in the 7.6S region that mediate regulation of SP-B mRNA stability. The 7.6S region was found to be sufficient for DEX-mediated stabilization of mRNA. Sequential substitution mutagenesis of the 7.6S region indicates that a 90-nt region is required for DEX-mediated stabilization and maintenance of intrinsic stability. In this region, one 30-nt-long element (002), predicted to form a stem-loop structure, is sufficient for DEX-mediated stabilization of mRNA and intrinsic mRNA stability. Cytosolic proteins specifically bind element 002, and binding activity is unaffected whether proteins are isolated from cells incubated in the absence or presence of DEX. While loop sequences of element 002 have no role in regulation of SP-B mRNA stability, the proximal stem sequences are required for DEX-mediated stabilization and specific binding of proteins. Mutation of the sequences that comprise the proximal or distal arm of the stem negates the destabilizing activity of element 002 on intrinsic SP-B mRNA stability. These results indicate that cytosolic proteins bind a single hairpin structure that mediates intrinsic and hormonal regulation of SP-B mRNA stability via mechanisms that involve sequences of the stems of the hairpin structure.

Cis-acting lnc-Cxcl2 restrains neutrophil-mediated lung inflammation by inhibiting epithelial cell CXCL2 expression in virus infection

2021 ◽  
Vol 118 (41) ◽  
pp. e2108276118
Author(s):  
Shuo Liu ◽  
Jiaqi Liu ◽  
Xue Yang ◽  
Minghong Jiang ◽  
Qingqing Wang ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Virus Infection ◽  
Viral Infection ◽  
Rna Binding ◽  
Influenza Virus Infection ◽  
Lung Epithelial Cells ◽  
Mouse Lung ◽  
Chemokine Production ◽  
Lung Epithelial

Chemokine production by epithelial cells is important for neutrophil recruitment during viral infection, the appropriate regulation of which is critical for restraining inflammation and attenuating subsequent tissue damage. Epithelial cell expression of long noncoding RNAs (lncRNAs), RNA-binding proteins, and their functional interactions during viral infection and inflammation remain to be fully understood. Here, we identified an inducible lncRNA in the Cxcl2 gene locus, lnc-Cxcl2, which could selectively inhibit Cxcl2 expression in mouse lung epithelial cells but not in macrophages. lnc-Cxcl2–deficient mice exhibited increased Cxcl2 expression, enhanced neutrophils recruitment, and more severe inflammation in the lung after influenza virus infection. Mechanistically, nucleus-localized lnc-Cxcl2 bound to Cxcl2 promoter, recruited a ribonucleoprotein La, which inhibited the chromatin accessibility of chemokine promoters, and consequently inhibited Cxcl2 transcription in cis. However, unlike mouse lnc-Cxcl2, human lnc-CXCL2-4-1 inhibited multiple immune cytokine expressions including chemokines in human lung epithelial cells. Together, our results demonstrate a self-protecting mechanism within epithelial cells to restrain chemokine and neutrophil-mediated inflammation, providing clues for better understanding chemokine regulation and epithelial cell function in lung viral infection.

scholarly journals Effect of Slit/Robo signaling on regeneration in lung emphysema

2021 ◽  
Author(s):  
Jin-Soo Park ◽  
RyeonJin Cho ◽  
Eun-Young Kang ◽  
Yeon-Mok Oh
Keyword(s):  
Epithelial Cells ◽  
Mouse Model ◽  
Lung Epithelial Cells ◽  
Mouse Lung ◽  
Chronic Obstructive ◽  
Irreversible Damage ◽  
Lung Epithelial ◽  
And Migration ◽  
Proliferation And Migration

AbstractEmphysema, a pathological component of chronic obstructive pulmonary disease, causes irreversible damage to the lung. Previous studies have shown that Slit plays essential roles in cell proliferation, angiogenesis, and organ development. In this study, we evaluated the effect of Slit2 on the proliferation and migration of mouse lung epithelial cells and its role in regeneration in an emphysema lung mouse model. Here, we have shown that Slit2/Robo signaling contributes to the regeneration of lungs damaged by emphysema. Mouse epithelial lung cells treated with Slit2 exhibited increased proliferation and migration in vitro. Our results also showed that Slit2 administration improved alveolar regeneration in the emphysema mouse model in vivo. Furthermore, Slit2/Robo signaling increased the phosphorylation of ERK and Akt, which was mediated by Ras activity. These Slit2-mediated cellular signaling processes may be involved in the proliferation and migration of mouse lung epithelial cells and are also associated with the potential mechanism of lung regeneration. Our findings suggest that Slit2 administration may be beneficial for alveolar regeneration in lungs damaged by emphysema.

Nitric oxide increases IL-8 gene transcription and mRNA stability to enhance IL-8 gene expression in lung epithelial cells

2004 ◽  
Vol 287 (4) ◽  
pp. L764-L773 ◽  
Author(s):  
Loretta Sparkman ◽  
Vijayakumar Boggaram
Keyword(s):  
Gene Expression ◽  
Nitric Oxide ◽  
Protein Kinase ◽  
Epithelial Cells ◽  
Gene Transcription ◽  
Mrna Stability ◽  
Inflammatory Responses ◽  
Lung Epithelial Cells ◽  
Mrna Levels ◽  
Lung Epithelial

Interleukin (IL)-8, a C-X-C chemokine, is a potent chemoattractant and an activator for neutrophils, T cells, and other immune cells. The airway and respiratory epithelia play important roles in the initiation and modulation of inflammatory responses via production of cytokines and surfactant. The association between elevated levels of nitric oxide (NO) and IL-8 in acute lung injury associated with sepsis, acute respiratory distress syndrome, respiratory syncytial virus infection in infants, and other inflammatory diseases suggested that NO may play important roles in the control of IL-8 gene expression in the lung. We investigated the role of NO in the control of IL-8 gene expression in H441 lung epithelial cells. We found that a variety of NO donors significantly induced IL-8 mRNA levels, and the increase in IL-8 mRNA was associated with an increase in IL-8 protein. NO induction of IL-8 mRNA was due to increases in IL-8 gene transcription and mRNA stability. NO induction of IL-8 mRNA levels was not inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one and KT-5823, inhibitors of soluble guanylate cyclase and protein kinase G, respectively, and 8-bromo-cGMP did not increase IL-8 mRNA levels. This indicated that NO induces IL-8 mRNA levels independently of changes in the intracellular cGMP levels. NO induction of IL-8 mRNA was significantly reduced by inhibitors of extracellular regulated kinase and protein kinase C. IL-8 induction by NO was also reduced by hydroxyl radical scavengers such as dimethyl sulfoxide and dimethylthiourea, indicating the involvement of hydroxyl radicals in the induction process. NO induction of IL-8 gene expression could be a significant contributing factor in the initiation and induction of inflammatory response in the respiratory epithelium.

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