Interleukin-13 Induces Tissue Fibrosis by Selectively Stimulating and Activating Transforming Growth Factor β1
By C. Lee, R. Homer, Zhou Zhu, S. Lanone, Xiaoman Wang, V. Koteliansky, J. Shipley, P. Gotwals, P. Noble, Qingsheng Chen and 2 more. Journal of Experimental Medicine, 2001
993 citations recorded by the source corpus.
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.
Subfields: Immunology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/f8a934ab993d19e2126407302ef4753a06f3ba91
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In Pulmonary and Respiratory Medicine
Citations in the corpus
- Macrophages: Master Regulators of Inflammation and Fibrosis (2010, background): “60 Regardless of the exact mechanism of action of OPN, these studies nicely illustrate that macrophages regulate fibrosis via mechanisms that are distinct from TGF-b1.”
- Integrating mechanisms of pulmonary fibrosis (2011, background): “Mechanistically, NOX4 is required for TGF-1–induced myofibroblast differentiation, ECM synthesis, and fibroblast contractility.”
- Pathogenetic mechanisms in radiation fibrosis. (2010, background): “profibrotic IL-4 and IL-13 released by Thy-2 lymphocytes and antifibrotic IL-1 and IL-12 produced by the Thy-1 lymphocyte subset determines whether fibrosis or repair/regeneration dominates some organ responses to injury [22,41,42].”
- Macrophages and Tissue Injury: Agents of Defense or Destruction? (2011, background): “Additional support comes from findings that administration of the M2 inducer IL-10 or IL-13 protects mice from acetaminophen-induced hepatotoxicity and lethal endotoxemia, whereas transgenic mice lacking the gene for CCR2, IL-10, IL-13, or IL-4 plus IL-10 and wild-type mice treated with anti-IL-13 a”
- The immunobiology of schistosomiasis (2002, background): “The mechanism by which IL-13 is able to promote fibrogenesis has been elucidated in a series of recent studie”
- Cellular and molecular mechanisms of fibrosis (2008, background): “TGFβ1 is stored inside the cell as a disulphide-bonded homodimer, non-covalently bound to a latency-associated protein (LAP), which keeps TGFβ inactive.”
- Protective and pathogenic functions of macrophage subsets (2011, background): “, which have been shown to induce and activate the pro-fibrotic cytokine TGFβ1 in macrophages through an IL-13- and MMP9-dependent mechanis”