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Influence of the cystic fibrosis transmembrane conductance regulator on expression of lipid metabolism-related genes in dendritic cells.

Xu Y, Tertilt C, Krause A, Quadri LE, Crystal RG, Worgall S - Respir. Res. (2009)

Bottom Line: Gene expression analysis in DC generated from naive CF and WT mice revealed decreased expression of Caveolin-1 (Cav1), a membrane lipid raft protein, in the CF DC compared to WT DC.Following exposure to P. aeruginosa, expression of 3beta-hydroxysterol-Delta7 reductase (Dhcr7) and stearoyl-CoA desaturase 2 (Scd2), two enzymes involved in the lipid metabolism that are also regulated by SREBP, was less decreased in the CF DC compared to WT DC.These results suggest that CFTR dysfunction in DC affects factors involved in membrane structure and lipid-metabolism, which may contribute to the abnormal inflammatory and immune response characteristic of CF.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, Weill Cornell Medical College, New York, USA. yax2002@med.cornell.edu

ABSTRACT

Background: Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Infections of the respiratory tract are a hallmark in CF. The host immune responses in CF are not adequate to eradicate pathogens, such as P. aeruginosa. Dendritic cells (DC) are crucial in initiation and regulation of immune responses. Changes in DC function could contribute to abnormal immune responses on multiple levels. The role of DC in CF lung disease remains unknown.

Methods: This study investigated the expression of CFTR gene in bone marrow-derived DC. We compared the differentiation and maturation profile of DC from CF and wild type (WT) mice. We analyzed the gene expression levels in DC from naive CF and WT mice or following P. aeruginosa infection.

Results: CFTR is expressed in DC with lower level compared to lung tissue. DC from CF mice showed a delayed in the early phase of differentiation. Gene expression analysis in DC generated from naive CF and WT mice revealed decreased expression of Caveolin-1 (Cav1), a membrane lipid raft protein, in the CF DC compared to WT DC. Consistently, protein and activity levels of the sterol regulatory element binding protein (SREBP), a negative regulator of Cav1 expression, were increased in CF DC. Following exposure to P. aeruginosa, expression of 3beta-hydroxysterol-Delta7 reductase (Dhcr7) and stearoyl-CoA desaturase 2 (Scd2), two enzymes involved in the lipid metabolism that are also regulated by SREBP, was less decreased in the CF DC compared to WT DC.

Conclusion: These results suggest that CFTR dysfunction in DC affects factors involved in membrane structure and lipid-metabolism, which may contribute to the abnormal inflammatory and immune response characteristic of CF.

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Related in: MedlinePlus

Differentiation and maturation of DC from CF mice. Differentiation and maturation of DC (CD11c+) from WT (gray) and CF (black) mice were monitored over time analyzing the surface expression of CD40, CD40L, CD80, CD86, MHCI, MHCII and ICAM. The y-axis represents the percentage expression of each marker in the CD11c population. Data from day 2 (A) and day 8 (B) are presented. Shown is the mean ± SEM of three different samples. *denotes p < 0.05.
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Figure 3: Differentiation and maturation of DC from CF mice. Differentiation and maturation of DC (CD11c+) from WT (gray) and CF (black) mice were monitored over time analyzing the surface expression of CD40, CD40L, CD80, CD86, MHCI, MHCII and ICAM. The y-axis represents the percentage expression of each marker in the CD11c population. Data from day 2 (A) and day 8 (B) are presented. Shown is the mean ± SEM of three different samples. *denotes p < 0.05.

Mentions: In order to evaluate if the impaired CFTR expression in CF DC influences their differentiation profile, bone marrow cells were analyzed an day 0, 2, 4, 6 and 8 using the differentiation and maturation markers CD40, CD40L, CD80, CD86, ICAM, MHCI and MHCII. No quantitative or qualitative differences in the primary CD11c+ bone marrow population between WT and CF mice were observed (data not shown). On day 2 there was a delay in the upregulation of CD40, CD80 and CD86 expression in the bone marrow culture of CF mice (p < 0.05, Figure 3A) whereas CD40L was increased in CF DC compared to the WT DC. On day 8, these differences were not observed anymore and the mature DC from the WT and CF mice expressed all markers comparably (Figure 3B).


Influence of the cystic fibrosis transmembrane conductance regulator on expression of lipid metabolism-related genes in dendritic cells.

Xu Y, Tertilt C, Krause A, Quadri LE, Crystal RG, Worgall S - Respir. Res. (2009)

Differentiation and maturation of DC from CF mice. Differentiation and maturation of DC (CD11c+) from WT (gray) and CF (black) mice were monitored over time analyzing the surface expression of CD40, CD40L, CD80, CD86, MHCI, MHCII and ICAM. The y-axis represents the percentage expression of each marker in the CD11c population. Data from day 2 (A) and day 8 (B) are presented. Shown is the mean ± SEM of three different samples. *denotes p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2683168&req=5

Figure 3: Differentiation and maturation of DC from CF mice. Differentiation and maturation of DC (CD11c+) from WT (gray) and CF (black) mice were monitored over time analyzing the surface expression of CD40, CD40L, CD80, CD86, MHCI, MHCII and ICAM. The y-axis represents the percentage expression of each marker in the CD11c population. Data from day 2 (A) and day 8 (B) are presented. Shown is the mean ± SEM of three different samples. *denotes p < 0.05.
Mentions: In order to evaluate if the impaired CFTR expression in CF DC influences their differentiation profile, bone marrow cells were analyzed an day 0, 2, 4, 6 and 8 using the differentiation and maturation markers CD40, CD40L, CD80, CD86, ICAM, MHCI and MHCII. No quantitative or qualitative differences in the primary CD11c+ bone marrow population between WT and CF mice were observed (data not shown). On day 2 there was a delay in the upregulation of CD40, CD80 and CD86 expression in the bone marrow culture of CF mice (p < 0.05, Figure 3A) whereas CD40L was increased in CF DC compared to the WT DC. On day 8, these differences were not observed anymore and the mature DC from the WT and CF mice expressed all markers comparably (Figure 3B).

Bottom Line: Gene expression analysis in DC generated from naive CF and WT mice revealed decreased expression of Caveolin-1 (Cav1), a membrane lipid raft protein, in the CF DC compared to WT DC.Following exposure to P. aeruginosa, expression of 3beta-hydroxysterol-Delta7 reductase (Dhcr7) and stearoyl-CoA desaturase 2 (Scd2), two enzymes involved in the lipid metabolism that are also regulated by SREBP, was less decreased in the CF DC compared to WT DC.These results suggest that CFTR dysfunction in DC affects factors involved in membrane structure and lipid-metabolism, which may contribute to the abnormal inflammatory and immune response characteristic of CF.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, Weill Cornell Medical College, New York, USA. yax2002@med.cornell.edu

ABSTRACT

Background: Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Infections of the respiratory tract are a hallmark in CF. The host immune responses in CF are not adequate to eradicate pathogens, such as P. aeruginosa. Dendritic cells (DC) are crucial in initiation and regulation of immune responses. Changes in DC function could contribute to abnormal immune responses on multiple levels. The role of DC in CF lung disease remains unknown.

Methods: This study investigated the expression of CFTR gene in bone marrow-derived DC. We compared the differentiation and maturation profile of DC from CF and wild type (WT) mice. We analyzed the gene expression levels in DC from naive CF and WT mice or following P. aeruginosa infection.

Results: CFTR is expressed in DC with lower level compared to lung tissue. DC from CF mice showed a delayed in the early phase of differentiation. Gene expression analysis in DC generated from naive CF and WT mice revealed decreased expression of Caveolin-1 (Cav1), a membrane lipid raft protein, in the CF DC compared to WT DC. Consistently, protein and activity levels of the sterol regulatory element binding protein (SREBP), a negative regulator of Cav1 expression, were increased in CF DC. Following exposure to P. aeruginosa, expression of 3beta-hydroxysterol-Delta7 reductase (Dhcr7) and stearoyl-CoA desaturase 2 (Scd2), two enzymes involved in the lipid metabolism that are also regulated by SREBP, was less decreased in the CF DC compared to WT DC.

Conclusion: These results suggest that CFTR dysfunction in DC affects factors involved in membrane structure and lipid-metabolism, which may contribute to the abnormal inflammatory and immune response characteristic of CF.

Show MeSH
Related in: MedlinePlus