Interleukin-13 Induces Tissue Fibrosis by Selectively Stimulating and Activating Transforming Growth Factor β1

TLDR

Interleukin‑13 is a central mediator of tissue fibrosis driven by Th2 inflammation. The study tested whether IL‑13’s fibrogenic effects are mediated through transforming growth factor‑β. Researchers compared TGF‑β regulation in lung tissue from wild‑type mice and CC10‑IL‑13 transgenic mice that develop pulmonary fibrosis. IL‑13 selectively stimulated and activated TGF‑β1 in macrophages, an effect dependent on plasmin/serine protease activity and MMP‑9 but independent of CD44, and blocking TGF‑β1 signaling with sTGFβR‑Fc markedly reduced fibrosis.

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.