TY - JOUR
T1 - Thrombin and TNF-α/IL-1β synergistically induce fibroblast-mediated collagen gel degradation
AU - Fang, Qiuhong
AU - Liu, Xiangde
AU - Al-Mugotir, Mona
AU - Kobayashi, Tetsu
AU - Abe, Shinji
AU - Kohyama, Tadashi
AU - Rennard, Stephen I.
PY - 2006/12
Y1 - 2006/12
N2 - Degradation of preexisting and newly synthesized extracellular matrix is thought to play an important role in tissue remodeling. The current study evaluated whether thrombin and TNF-α/IL-1β could collaboratively induce collagen degradation by human fetal lung fibroblasts (HFL-1) and adult bronchial fibroblasts cultured in three-dimensional collagen gels. TNF-α/IL-1β alone induced production of matrix metalloproteinases (MMPs)-1, -3, and -9, which were released in latent form. With the addition of thrombin, the latent MMPs were converted into active forms and this resulted in collagen gel degradation. Part of the activation of MMPs by thrombin resulted from direct activation of MMP-1, MMP-2, MMP-3, and MMP-9 in the absence of cells. In addition, tissue inhibitor of metalloproteinase-1 production was inhibited by the combination of thrombin and TNF-α/ IL-1β. These results suggest that thrombin and TNF-α/IL-1β synergize to induce degradation of three-dimensional collagen gels through increasing the production and activation of MMPs, and that this effect is mediated through both direct activation of MMPs by thrombin and indirectly by thrombin activation of fibroblasts. Through such mechanisms, thrombin could contribute to many chronic lung disorders characterized by tissue remodeling.
AB - Degradation of preexisting and newly synthesized extracellular matrix is thought to play an important role in tissue remodeling. The current study evaluated whether thrombin and TNF-α/IL-1β could collaboratively induce collagen degradation by human fetal lung fibroblasts (HFL-1) and adult bronchial fibroblasts cultured in three-dimensional collagen gels. TNF-α/IL-1β alone induced production of matrix metalloproteinases (MMPs)-1, -3, and -9, which were released in latent form. With the addition of thrombin, the latent MMPs were converted into active forms and this resulted in collagen gel degradation. Part of the activation of MMPs by thrombin resulted from direct activation of MMP-1, MMP-2, MMP-3, and MMP-9 in the absence of cells. In addition, tissue inhibitor of metalloproteinase-1 production was inhibited by the combination of thrombin and TNF-α/ IL-1β. These results suggest that thrombin and TNF-α/IL-1β synergize to induce degradation of three-dimensional collagen gels through increasing the production and activation of MMPs, and that this effect is mediated through both direct activation of MMPs by thrombin and indirectly by thrombin activation of fibroblasts. Through such mechanisms, thrombin could contribute to many chronic lung disorders characterized by tissue remodeling.
KW - Collagen degradation
KW - Matrix metalloproteinase
KW - Thrombin
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UR - http://www.scopus.com/inward/citedby.url?scp=33845403077&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2005-0026OC
DO - 10.1165/rcmb.2005-0026OC
M3 - Article
C2 - 16858010
AN - SCOPUS:33845403077
VL - 35
SP - 714
EP - 721
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 6
ER -