TY - JOUR
T1 - Lipoprotein receptor-related protein 1 regulates collagen 1 expression, proteolysis, and migration in human pleural mesothelial cells
AU - Tucker, Torry A.
AU - Williams, LaTerrica
AU - Koenig, Kathleen
AU - Kothari, Hema
AU - Komissarov, Andrey A.
AU - Florova, Galina
AU - Mazar, Andrew P.
AU - Allen, Timothy C.
AU - Bdeir, Khalil
AU - Rao, L. Vijaya Mohan
AU - Idell, Steven
PY - 2012/2/1
Y1 - 2012/2/1
N2 - The low-density lipoprotein receptor-related protein 1 (LRP-1) binds and can internalize a diverse group of ligands, including members of the fibrinolytic pathway, urokinase plasminogen activator (uPA), and its receptor, uPAR. In this study, we characterized the role of LRP-1 in uPAR processing, collagen synthesis, proteolysis, and migration in pleural mesothelial cells (PMCs). When PMCs were treated with the proinflammatory cytokines TNF-α and IL-1β, LRP-1 significantly decreased at the mRNA and protein levels (70 and 90%, respectively; P <, 0.05). Consequently, uPA-mediated uPAR internalization was reduced by 80%in the presence of TNF-α or IL-1β (P< 0.05). In parallel studies, LRP-1 neutralization with receptor-associated protein (RAP) significantly reduced uPA-dependent uPAR internalization and increased uPAR stability in PMCs. LRP-1-deficient cells demonstrated increased uPAR t 1/2 versus LRP-1-expressing PMCs. uPA enzymatic activity was also increased in LRP-1-deficient and neutralized cells, and RAP potentiated uPA-dependent migration in PMCs. Collagen expression in PMCs was also induced by uPA, and the effect was potentiated in RAP-treated cells. These studies indicate that TNF-α and IL-1β regulate LRP-1 in PMCs and that LRP-1 thereby contributes to a range of pathophysiologically relevant responses of these cells.
AB - The low-density lipoprotein receptor-related protein 1 (LRP-1) binds and can internalize a diverse group of ligands, including members of the fibrinolytic pathway, urokinase plasminogen activator (uPA), and its receptor, uPAR. In this study, we characterized the role of LRP-1 in uPAR processing, collagen synthesis, proteolysis, and migration in pleural mesothelial cells (PMCs). When PMCs were treated with the proinflammatory cytokines TNF-α and IL-1β, LRP-1 significantly decreased at the mRNA and protein levels (70 and 90%, respectively; P <, 0.05). Consequently, uPA-mediated uPAR internalization was reduced by 80%in the presence of TNF-α or IL-1β (P< 0.05). In parallel studies, LRP-1 neutralization with receptor-associated protein (RAP) significantly reduced uPA-dependent uPAR internalization and increased uPAR stability in PMCs. LRP-1-deficient cells demonstrated increased uPAR t 1/2 versus LRP-1-expressing PMCs. uPA enzymatic activity was also increased in LRP-1-deficient and neutralized cells, and RAP potentiated uPA-dependent migration in PMCs. Collagen expression in PMCs was also induced by uPA, and the effect was potentiated in RAP-treated cells. These studies indicate that TNF-α and IL-1β regulate LRP-1 in PMCs and that LRP-1 thereby contributes to a range of pathophysiologically relevant responses of these cells.
KW - Half-life
KW - Internalization
KW - LRP-1
KW - Pleural mesothelial cells
KW - uPAR
UR - http://www.scopus.com/inward/record.url?scp=84856648815&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84856648815&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2011-0071OC
DO - 10.1165/rcmb.2011-0071OC
M3 - Article
C2 - 22298529
AN - SCOPUS:84856648815
SN - 1044-1549
VL - 46
SP - 196
EP - 206
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 2
ER -