Effect of activation of viral receptors on the gelatinases MMP-2 and MMP-9 in human mesothelial cells.
BACKGROUND
Extracellular matrix (ECM) not only provides molecular and spatial information that influence cell proliferation, differentiation and apoptosis but also has the potential to bind and present or release cytokines and cytotactic factors. Synthesis and degradation of extracellular matrix components are balanced by matrix metalloproteinases (MMP) and their inhibitors. In the pericardium as well as in the pleural and peritoneal cavities a multitude of clinically relevant disease states ranging from inflammation to fibrosis and tumor invasion result from altered regulation of MMP activity and are known to be associated with viral disease.


METHODS
Therefore, the functional linkage between viral receptors of the innate immune system, the toll-like receptors (TLR), and control of MMP activity was exemplarily analyzed by stimulating human mesothelial cells with poly (I:C) RNA.


RESULTS
We hereby show that human mesothelial cells (MC) express TLR3. After stimulation of MC with the cytokines TNF-alpha, IL-1beta and IFN-gamma alone or in combination to simulate a proinflammatory milieu as would occur during immune-mediated inflammatory disease, an upregulation of TLR3 is seen. Furthermore, a selectively TLR3 mediated, time- and dose-dependent upregulation of MMP-9 and TIMP-1 is found, whereas MMP-2 expression is not significantly affected by TLR3 stimulation.


CONCLUSIONS
With these results we provide evidence for a mechanism by which infectious agents can mediate processes of the final common path of inflammation as fibrosis via regulation of MMP and TIMP.
Merkle
Monika
M
Nephrologie, Klinikum Traunstein, Traunstein, Germany.
Ribeiro
Andrea
A
Sauter
Matthias
M
Ladurner
Roland
R
Mussack
Thomas
T
Sitter
Thomas
T
Wörnle
Markus
M
D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D011070:Poly I-C / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D011971:Receptors, Immunologic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*
D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; C495344:TLR3 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D051196:Toll-Like Receptor 3; D012313:RNA; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D011070:Poly I-C