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

نویسندگان

  • Chun Geun Lee
  • Robert J. Homer
  • Zhou Zhu
  • Sophie Lanone
  • Xiaoman Wang
  • Victor Koteliansky
  • J. Michael Shipley
  • Philip Gotwals
  • Paul Noble
  • Qingsheng Chen
  • Robert M. Senior
  • Jack A. Elias
چکیده

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.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Transforming Growth Factor-β1 Antagonizes Interleukin-5 Pro-Survival Signaling by Activating Calpain-1 in Primary Human Eosinophils.

BACKGROUND Eosinophils rapidly undergo apoptosis unless exposed to prosurvival cytokines such as interleukin 5 (IL-5) or granulocyte-macrophage colony stimulating factor (GM-CSF). In vivo, eosinophils are exposed to TGF-β 1 which can induce apoptosis suggesting it may function to counteract the effects of IL-5 or GM-CSF and limit, in vivo tissue eosinophilia. OBJECTIVE The objective of this s...

متن کامل

Transforming Growth Factor-β1 Preserves Bovine Nasal Cartilage against Degradation Induced by Interleukin-1α in Explant Culture

Background and Aims: Chondrocytes and their differentiation play a central role in joint diseases. Effect of the transforming growth factor (TGF)-β1 on chondrocyte characteristics and differentiation is not clearly understood. This study was undertaken to investigate the effects of TGF-β1 on tissue characteristics and morphology of chondrocytes against degradation induced by interleuk...

متن کامل

Interleukin-13 induces collagen type-1 expression through matrix metalloproteinase-2 and transforming growth factor-β1 in airway fibroblasts in asthma.

Airway remodelling is a feature of asthma that contributes to loss of lung function. One of the central components of airway remodelling is subepithelial fibrosis. Interleukin (IL)-13 is a key T-helper 2 cytokine and is believed to be the central mediator of allergic asthma including remodelling, but the mechanism driving the latter has not been elucidated in human asthma. We hypothesised that ...

متن کامل

Hypoxia drives the transition of human dermal fibroblasts to a myofibroblast-like phenotype via the TGF-β1/Smad3 pathway

Keloids, partially considered as benign tumors, are characterized by the overgrowth of fibrosis beyond the boundaries of the wound and are regulated mainly by transforming growth factor (TGF)-β1, which induces the transition of fibroblasts to myofibroblasts. Hypoxia is an important driving force in the development of lung and liver fibrosis by activating hypoxia inducible factor-1α and stimulat...

متن کامل

Comparison of a Suggested Model of Fibrosis in Human Dermal Fibroblasts by Serum from Systemic Sclerosis Patients with Transforming Growth Factor β Induced in vitro Model

Systemic sclerosis (SSc) is a chronic autoimmune disease, featuring fibrosis in multiple organs. The serum from SSc patients contain inflammatory mediators, contributing to SSc pathogenesis and could be used to develop cell culture models. Here, we compared the fibrotic effects of serum samples from SSc patients with TGFβ1 on human dermal fibroblasts (HDFs). HDF cells were cultured in four diff...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • The Journal of Experimental Medicine

دوره 194  شماره 

صفحات  -

تاریخ انتشار 2001