Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1)

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 I L-13 are mediated by transforming growth factor (TGF)-beta. To test this hy pothesis we compared the regulation of TGF-beta in lungs from wild-type mic e and CC10-IL-13 mice in which IL-13 overexpression causes pulmonary fibros is. IL-13 selectively stimulated TGF-beta (1) production in transgenic anim als and macrophages were the major site of TGF-beta (1) production and depo sition in these tissues. IL-13 also activated TGF-beta (1) in vivo. This ac tivation was associated with decreased levels of mRNA encoding latent TGF-b eta -binding protein-1 and increased MRNA encoding urinary plasminogen acti vator, matrix metalloproteinase (MMP)-9, and CD44. TGF-beta (1) activation was abrogated by the plasmin/serine protease antagonist aprotinin. It was a lso 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 fibros is was also significantly ameliorated by treatment with the TGF-beta antago nist soluble TGF betaR-Fc (sTGF betaR-Fc). These studies demonstrate that I L-13 is a potent stimulator and activator of TGF-beta (1) in vivo. They als o demonstrate that this activation is mediated by a plasmin/serine protease - and MMP-9-dependent and CD44-independent mechanism(s) and that the fibrog enic effects of IL-13 are mediated, in great extent, by this TGF-beta pathw ay.