Abstract
Interleukin (IL)-13 is a key mediator of tissue fibrosis caused by T helper cell type 2 inflammation. We hypothesized that the fibrogenic effects of IL-13 are mediated by transforming growth factor (TGF)-β. To test this hypothesis we compared the regulation of TGF-β in lungs from wild-type mice and CC10-IL-13 mice in which IL-13 overexpression causes pulmonary fibrosis. IL-13 selectively stimulated TGF-β1, production in transgenic animals and macrophages were the major site of TGF-β1, production and deposition in these tissues. IL-13 also activated TGF-β1, in vivo. This activation was associated with decreased levels of mRNA encoding latent TGF-Β-binding protein-1 and increased mRNA encoding urinary plasminogen activator, matrix metalloproteinase (MMP)-9, and CD44. TGF-β1 activation was abrogated by the plasmin/serine protease antagonist aprotinin. It was also decreased in progeny of crosses of CC10-IL-13 mice and MMP-9 null mice but was not altered in crosses with CD44 null animals. IL-13-induced fibrosis was also significantly ameliorated by treatment with the TGF-β antagonist soluble TGFβR-Fc (sTGFβR-Fc). These studies demonstrate that IL-13 is a potent stimulator and activator of TGF-β1, in vivo. They also demonstrate that this activation is mediated by a plasmin/serine protease- and MMP-9-dependent and CD44-independent mechanism(s) and that the fibrogenic effects of IL-13 are mediated, in great extent, by this TGF-β pathway.
Original language | English (US) |
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Pages (from-to) | 809-821 |
Number of pages | 13 |
Journal | Journal of Experimental Medicine |
Volume | 194 |
Issue number | 6 |
DOIs | |
State | Published - Sep 17 2001 |
Externally published | Yes |
Keywords
- Asthma
- CD44
- Lung
- Matrix metalloproteinase-9
- Plasmin
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology