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 IL-13 are mediated by transforming growth factor (TGF)-beta. To test this hypothesis we compared the regulation of TGF-beta in lungs from wild-type mice and CC10-IL-13 mice in which IL-13 overexpression causes pulmonary fibrosis. IL-13 selectively stimulated TGF-beta(1) production in transgenic animals and macrophages were the major site of TGF-beta(1) production and deposition in these tissues. IL-13 also activated TGF-beta(1) in vivo. This activation was associated with decreased levels of mRNA encoding latent TGF-beta-binding protein-1 and increased mRNA encoding urinary plasminogen activator, matrix metalloproteinase (MMP)-9, and CD44. TGF-beta(1) 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-beta antagonist soluble TGFbetaR-Fc (sTGFbetaR-Fc). These studies demonstrate that IL-13 is a potent stimulator and activator of TGF-beta(1) 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-beta pathway.
Lee
C G
CG
Yale University School of Medicine, Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, New Haven, CT 06520-8057, USA.
Homer
R J
RJ
Zhu
Z
Z
Lanone
S
S
Wang
X
X
Koteliansky
V
V
Shipley
J M
JM
Gotwals
P
P
Noble
P
P
Chen
Q
Q
Senior
R M
RM
Elias
J A
JA
D000818:Animals; D018960:Hyaluronan Receptors / Q000502:physiology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology*; D020780:Matrix Metalloproteinase 9 / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011658:Pulmonary Fibrosis / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology
D018960:Hyaluronan Receptors; D018793:Interleukin-13; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9