Interleukin-13 augments transforming growth factor-beta1-induced tissue inhibitor of metalloproteinase-1 expression in primary human airway fibroblasts

Am J Physiol Cell Physiol. 2005 Feb;288(2):C435-42. doi: 10.1152/ajpcell.00035.2004. Epub 2004 Sep 29.

Abstract

Tissue inhibitor of metalloproteinase (TIMP)-1 is a potent inhibitor of activated matrix metalloproteinases (MMPs) such as gelatinases and collagenases. TIMP-1 is induced by transforming growth factor-beta1 (TGF-beta1), but details regarding signaling pathways remain unclear. T-helper-2 cytokines also have profibrotic properties and can interact with TGF-beta. In the present study, we examined the effects of interleukin (IL)-13 (2,500 pM) on TGF-beta1 (200 pM)-induced expression of TIMP-1 mRNA and protein in primary human airway fibroblasts obtained from 57 human subjects. IL-13 alone had no effect on TIMP-1 mRNA or protein expression. However, IL-13 synergistically augmented TGF-beta1-induced TIMP-1 mRNA and protein expression (P < 0.001 vs. TGF-beta1 alone). The upregulation of TIMP-1 by the combination of TGF-beta1 and IL-13 involved increased transcription, with little effect on mRNA stabilization. Initial exploration of the pathways leading to the synergy determined that activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway by IL-13 may have a negative effect on TIMP-1 production. The specific PI3K inhibitor LY-294002 in the presence of TGF-beta1, IL-13, or the combination of the two caused significant increases in TIMP-1 mRNA expression, while LY-294002 increased TIMP-1 protein levels in the presence of IL-13 alone. These results suggest that IL-13 augments TGF-beta1-induced profibrotic responses at both the mRNA and protein levels. Although IL-13 induced activation of PI3K-Akt, the activation did not contribute to the synergy observed with TGF-beta1 plus IL-13 in TIMP-1 expression and in fact may dampen it. The mechanisms behind the synergy remain to be determined.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1-Phosphatidylinositol 4-Kinase / metabolism
  • Cells, Cultured
  • Drug Synergism
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism*
  • Humans
  • Interleukin-13 / metabolism
  • Interleukin-13 / pharmacology*
  • Lung / physiology
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Tissue Inhibitor of Metalloproteinase-1 / biosynthesis*
  • Tissue Inhibitor of Metalloproteinase-1 / drug effects
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology*

Substances

  • Interleukin-13
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-1
  • Transforming Growth Factor beta
  • 1-Phosphatidylinositol 4-Kinase