title: Effect of CFTR modifiers on arylsulfatase B activity in cystic fibrosis and normal human bronchial epithelial cells.
abstract: BACKGROUND
  The enzyme Arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase), is required for degradation of sulfated glycosaminoglycans (GAGs) which accumulate in cystic fibrosis. ARSB is reduced in cystic fibrosis cells and increases when defective CFTR is repaired by insertion of the normal gene. This study was undertaken to determine if modification of CFTR by small molecule correctors or potentiators could also increase ARSB and reduce the accumulation of chondroitin 4-sulfate (C4S).
  
  
  METHODS
  CF bronchial epithelial cells homozygous for the F508 deletion (ACD#14071) and normal human bronchial epithelial cells (BEC) were grown and differentiated following an established protocol. Cells were treated with either VRT-532, a CFTR potentiator, or VRT-534, a CFTR corrector, or vehicle control. The impact on ARSB activity, protein and mRNA expression, C4S and total sulfated glycosaminoglycan content, Interleukin-8 and Interleukin-6 secretion, and neutrophil chemotaxis was determined by specific assays.
  
  
  RESULTS
  The CFTR potentiator, but not the corrector, increased ARSB activity and expression to the level in the normal bronchial epithelial cells (BEC). Concomitantly, total sulfated glycosaminoglycans and C4S declined, secreted IL-8 increased, secreted IL-6 declined, and neutrophil chemotaxis to the spent media obtained from the potentiator-treated CF cells increased.
  
  
  CONCLUSIONS
  The CFTR potentiator increased ARSB activity and expression and associated effects. This suggests that a critical interaction between CFTR and ARSB is related to CFTR function in regulation of a ligand-gated anion channel at the cell membrane, rather than to CFTR processing and intracellular trafficking.
authors.affiliation: University of Illinois at Chicago, Chicago, IL 60612, USA; Jesse Brown VA Medical Center, Chicago, IL 60612, USA.
authors.forename: Sumit
authors.initials: S
authors.lastname: Bhattacharyya
authors.affiliation: University of Illinois at Chicago, Chicago, IL 60612, USA; Jesse Brown VA Medical Center, Chicago, IL 60612, USA.
authors.forename: Leo
authors.initials: L
authors.lastname: Feferman
authors.affiliation: University of Illinois at Chicago, Chicago, IL 60612, USA; Jesse Brown VA Medical Center, Chicago, IL 60612, USA. Electronic address: jkt@uic.edu.
authors.forename: Joanne K
authors.initials: JK
authors.lastname: Tobacman
mesh_terms: D001980:Bronchi / Q000187:drug effects*; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002809:Chondroitin Sulfates / Q000378:metabolism; D003408:Cresols / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000201:enzymology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects*; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects*
chemical_list: C508606:CXCL8 protein, human; D003408:Cresols; D006025:Glycosaminoglycans; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D011720:Pyrazoles; C535089:VRT 532; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002809:Chondroitin Sulfates; D020051:N-Acetylgalactosamine-4-Sulfatase
keywords: Arylsulfatase B; CFTR; Chondroitin 4-sulfate; Corrector; Cystic fibrosis; Glycosaminoglycans; Interleukin-6; Interleukin-8; Neutrophil migration; Potentiator