Effect of pro-inflammatory stimuli on mucin expression and inhibition by secretory leucoprotease inhibitor.
Stimuli-induced expression of certain mucin genes has been demonstrated to occur as a result of ligand-dependent activation of the epidermal growth factor receptor (EGFR). In particular, MUC5AC expression can be induced by cigarette-smoke, neutrophil elastase and lipopolysaccharide (LPS) following activation of tumour necrosis factor alpha-converting enzyme. We now show that a large of number of stimuli relevant to the cystic fibrosis lung - neutrophil elastase, LPS, Pam3Cys-Ser-(Lys)4 Hydrochloride (a lipopeptide analogue), CpG DNA (which mimics bacterial DNA) and cystic fibrosis bronchoalveolar lavage fluid - can activate MUC1 and 2 expression as well as MUC5AC expression in lung epithelial cells via an EGFR-dependent mechanism. In addition, we demonstrate that the immunomodulatory anti-protease, secretory leucoprotease inhibitor, can inhibit stimuli-induced MUC1, 2 and 5AC expression via a mechanism that is primarily dependent on the inhibition of transforming growth factor type alpha release. Therefore, mucin gene expression, induced by cystic fibrosis respiratory stimuli, can be inhibited by secretory leucoprotease inhibitor indicating its potential importance as an anti-mucin agent in cystic fibrosis and other chronic lung diseases characterized by mucus hypersecretion.
Griffin
Siobhan
S
Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
Carroll
Tomas P
TP
Greene
Catherine M
CM
O'Neill
Shane J
SJ
Taggart
Clifford C
CC
McElvaney
Noel G
NG
D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D019272:Leukocyte Elastase / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008954:Models, Biological; D009077:Mucins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000494:pharmacology*
D008070:Lipopolysaccharides; D009077:Mucins; D053481:Secretory Leukocyte Peptidase Inhibitor; D066246:ErbB Receptors; D019272:Leukocyte Elastase