Signaling events required for transforming growth factor-beta stimulation of connective tissue growth factor expression by cultured human lung fibroblasts

Arch Biochem Biophys. 2001 Nov 1;395(1):103-12. doi: 10.1006/abbi.2001.2571.

Abstract

It is possible that many of the fibrogenic effects of transforming growth factor-beta (TGF-beta) are mediated by connective tissue growth factor (CTGF). In the present work, we show that TGF-beta1 produces a 5- to 6-fold increase in CTGF expression by cultured human lung fibroblasts that is due mainly to increased transcription. The half-life of CTGF mRNA is 1.96 h, consistent with its role as a cytokine. In addition to requiring Smad activity, based upon the effects of specific inhibitors, the TGF-beta intracellular signaling pathway requires the activity of a phosphatidylcholine-specific phospholipase C, a protein kinase C, and one or more tyrosine kinases. It is also likely that the pathway requires a member of the Ras superfamily of small GTPases, but not trimeric G proteins. Pharmacologic inhibition of TGF-beta stimulation of CTGF expression may be an effective therapeutic approach to a variety of undesirable fibrotic reactions.

Publication types

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

MeSH terms

  • Cells, Cultured
  • Cholera Toxin / pharmacology
  • Connective Tissue Growth Factor
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Growth Substances / biosynthesis*
  • Growth Substances / genetics
  • Humans
  • Immediate-Early Proteins / biosynthesis*
  • Immediate-Early Proteins / genetics
  • Intercellular Signaling Peptides and Proteins*
  • Lung / cytology
  • Lung / drug effects
  • Lung / metabolism*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Protein Prenylation / drug effects
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • RNA, Messenger / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / pharmacology*
  • Transforming Growth Factor beta1
  • Type C Phospholipases / antagonists & inhibitors
  • Type C Phospholipases / metabolism
  • Virulence Factors, Bordetella / pharmacology
  • ras Proteins / metabolism

Substances

  • CCN2 protein, human
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Growth Substances
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • RNA, Messenger
  • TGFB1 protein, human
  • Trans-Activators
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Virulence Factors, Bordetella
  • Connective Tissue Growth Factor
  • Cholera Toxin
  • Protein-Tyrosine Kinases
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases
  • Type C Phospholipases
  • phosphatidylcholine-specific phospholipase C
  • ras Proteins