Regulation of proteolytic activity induced by inflammatory stimuli in lung epithelial cells.
A large number of chronic lung diseases such as asthma bronchiale are associated with alveolar and/or bronchial inflammation accompanied by a damage of the alveolocapillary barrier. In this process proteolytic mechanisms may play a crucial role. The aim of the present study was to assess the role of TNF-alpha on the proteolytic activity of pulmonary epithelial cells and to find possible intracellular signaling pathways which may mediate the effect of TNF-alpha. For our studies we have used the A549 human lung epithelial cell line. Plasminogen activator and metalloproteinase activity was measured using zymography. TNF-alpha induced a time and concentration dependent activation of the urokinase type plasminogen activator (u-PA) and tissue type plasminogen activator (t-PA) activity in A549 cells. This effect could be blocked completely by dexamethasone and was reduced significantly by the Rho-kinase inhibitor Y27632. Similarly, an increased activity in the culture medium of the 72 kDa MMP-2 in response to TNF-alpha could be observed as well. This could be reduced by dexamethasone and Y27632. Our results show that TNF-alpha is at least partly responsible for an increased proteolytic activity and beside corticosteroids Rho-kinase may constitute a potential target for future therapeutical approaches.
Szabó
H
H
Department of Paediatrics, Albert Szent-Györgyi Medical and Pharmaceutical Center, University of Szeged, 6720 Szeged, Hungary.
Novák
Z
Z
Bauer
H
H
Szatmári
E
E
Farkas
A
A
Wejksza
K
K
Orbók
A
A
Wilhelm
I
I
Krizbai
I A
IA
D002465:Cell Movement; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology / Q000502:physiology*; D008168:Lung / Q000166:cytology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015398:Signal Transduction; D013347:Subcellular Fractions; D013997:Time Factors; D010959:Tissue Plasminogen Activator; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator
D017077:Culture Media, Conditioned; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2