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-1 beta 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. (C) 2010 Elsevier B.V. All rights reserved.