title: IL-13-induced proliferation of airway epithelial cells: mediation by intracellular growth factor mobilization and ADAM17.
abstract: BACKGROUND
  The pleiotrophic cytokine interleukin (IL)-13 features prominently in allergic and inflammatory diseases. In allergic asthma, IL-13 is well established as an inducer of airway inflammation and tissue remodeling. We demonstrated previously that IL-13 induces release of transforming growth factor-alpha (TGFalpha) from human bronchial epithelial cells, with proliferation of these cells mediated by the autocrine/paracrine action of this growth factor. TGFalpha exists as an integral membrane protein and requires proteolytic processing to its mature form, with a disintegrin and metalloproteinase (ADAM)17 responsible for this processing in a variety of tissues.
  
  
  METHODS
  In this study, normal human bronchial epithelial (NHBE) cells grown in air/liquid interface (ALI) culture were used to examine the mechanisms whereby IL-13 induces release of TGFalpha and cellular proliferation. Inhibitors and antisense RNA were used to examine the role of ADAM17 in these processes, while IL-13-induced changes in the intracellular expression of TGFalpha and ADAM17 were visualized by confocal microscopy.
  
  
  RESULTS
  IL-13 was found to induce proliferation of NHBE cells, and release of TGFalpha, in an ADAM17-dependent manner; however, this IL-13-induced proliferation did not appear to result solely from ADAM17 activation. Rather, IL-13 induced a change in the location of TGFalpha expression from intracellular to apical regions of the NHBE cells. The apical region was also found to be a site of significant ADAM17 expression, even prior to IL-13 stimulation.
  
  
  CONCLUSIONS
  Results from this study indicate that ADAM17 mediates IL-13-induced proliferation and TGFalpha shedding in NHBE cells. Furthermore, they provide the first example wherein a cytokine (IL-13) induces a change in the intracellular expression pattern of a growth factor, apparently inducing redistribution of intracellular stores of TGFalpha to the apical region of NHBE cells where expression of ADAM17 is prominent. Thus, IL-13-induced, ADAM17-mediated release of TGFalpha, and subsequent epithelial cell proliferation, could contribute to the epithelial hypertrophy, as well as other features, associated with airway remodeling in allergic asthma.
authors.affiliation: Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA. boothbr@mail.nih.gov
authors.forename: Brian W
authors.initials: BW
authors.lastname: Booth
authors.forename: Tracy
authors.initials: T
authors.lastname: Sandifer
authors.forename: Erika L
authors.initials: EL
authors.lastname: Martin
authors.forename: Linda D
authors.initials: LD
authors.lastname: Martin
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000704:Analysis of Variance; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D018793:Interleukin-13 / Q000494:pharmacology*; D018613:Microscopy, Confocal; D011336:Probability; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects; D016211:Transforming Growth Factor alpha / Q000378:metabolism*
chemical_list: D018793:Interleukin-13; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors; D051722:ADAM Proteins