TNF regulates sialyl-Lewisx and 6-sulfo-sialyl-Lewisx expression in human lung through up-regulation of ST3GAL4 transcript isoform BX.
Bronchial mucins from severely infected patients suffering from lung diseases such as chronic bronchitis or cystic fibrosis exhibit increased amounts of sialyl-Lewis(x) (NeuAcα2-3Galβ1-4[Fucα1-3]GlcNAc-R, sLe(x)) glycan structures. In cystic fibrosis, sLe(x) and its sulfated form 6-sulfo-sialyl-Lewis(x) (NeuAcα2-3Galβ1-4[Fucα1-3](HO(3)S-6)GlcNAc-R, 6-sulfo-sLe(x)) serve as receptors for Pseudomonas aeruginosa and are involved in the chronicity of airway infection. However, little is known about the molecular mechanisms regulating the changes in glycosylation and sulfation of mucins in airways. Herein, we show that the pro-inflammatory cytokine TNF increases the expression of α2,3-sialyltransferase gene ST3GAL4, both in human bronchial mucosa and in A549 lung carcinoma cells. The role of sialyltransferase ST3Gal IV in sLe(x) biosynthesis was confirmed by siRNA silencing of ST3GAL4 gene. BX is the major transcript isoform expressed in healthy bronchial mucosa and in A549 cells, and is up-regulated by TNF in both models. Bioinformatics analysis and luciferase assays have confirmed that the 2 kb genomic sequence surrounding BX exon contains a promoter region regulated by TNF-related transcription factors. These results support further work aiming at the development of anti-inflammatory strategy to reduce chronic airway infection in diseases such as cystic fibrosis.
Université Lille Nord de France, Lille 1, UGSF, CNRS, UMR 8576, 59650 Villeneuve d'Ascq, France.
Florent
F
Colomb
Marie-Ange
MA
Krzewinski-Recchi
Fala
F
El Machhour
Eric
E
Mensier
Sophie
S
Jaillard
Agata
A
Steenackers
Anne
A
Harduin-Lepers
Jean-Jacques
JJ
Lafitte
Philippe
P
Delannoy
Sophie
S
Groux-Degroote
D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D006801:Humans; D016256:Lewis X Antigen / Q000096:biosynthesis / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D008168:Lung / Q000187:drug effects* / Q000378:metabolism*; D009092:Mucous Membrane / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009844:Oligosaccharides / Q000096:biosynthesis / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000080506:Sialyl Lewis X Antigen / Q000031:analogs & derivatives; D012799:Sialyltransferases / Q000172:deficiency / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
C086949:6'-sulfated sialyl Lewis x; D016256:Lewis X Antigen; D009844:Oligosaccharides; D012333:RNA, Messenger; D000080506:Sialyl Lewis X Antigen; D014409:Tumor Necrosis Factor-alpha; D008156:Luciferases; D012799:Sialyltransferases; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase; C000722087:ST3GAL1 protein, human