Hyper-responsiveness of IPF/UIP fibroblasts: interplay between TGFbeta1, IL-13 and CCL2

Int J Biochem Cell Biol. 2008;40(10):2174-82. doi: 10.1016/j.biocel.2008.02.016. Epub 2008 Feb 23.


One of the hallmarks of idiopathic pulmonary fibrosis with a usual interstitial pneumonia histological pathology (IPF/UIP) is excess collagen deposition, due to enhanced fibroblast extracellular matrix synthetic activity. Studies using murine models of lung fibrosis have elucidated a pro-fibrotic pathway involving IL-13 driving CCL2, which in turn drives TGFbeta1 in lung fibroblasts. Therefore, we sought to determine whether this pathway exists in the human fibrotic setting by evaluating human IPF/UIP fibroblasts. IPF/UIP fibroblasts have an increased baseline fibrotic phenotype compared to non-fibrotic fibroblasts. Interestingly, non-fibrotic fibroblasts responded in a pro-fibrotic manner to TGFbeta1 but were relatively non-responsive to IL-13 or CCL2, whereas, IPF/UIP cells were hyper-responsive to TGFbeta1, IL-13 and CCL2. Interestingly, TGFbeta1, CCL2 and IL-13 all upregulated TGFbeta receptor and IL-13 receptor expression, suggesting an ability of the mediators to modulate the function of each other. Furthermore, in vivo, neutralization of both JE and MCP5, the two functional orthologs of CCL2, during bleomycin-induced pulmonary fibrosis significantly reduced collagen deposition as well as JE and CCR2 expression. Also in the bleomycin model, CTGF, which is highly induced following TGFbeta stimulation, was attenuated with anti-JE/anti-MCP5 treatment. Overall this study demonstrates an interplay between TGFbeta1, IL-13 and CCL2 in IPF/UIP, where these three mediators feedback on each other, promoting the fibrotic response.

MeSH terms

  • Actins / metabolism
  • Animals
  • Antibodies / pharmacology
  • Cell Line
  • Chemokine CCL2 / pharmacology*
  • Collagen / biosynthesis
  • Female
  • Fibroblasts / drug effects*
  • Fibroblasts / pathology*
  • Gene Expression Regulation / drug effects
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Interleukin-13 / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Monocyte Chemoattractant Proteins / metabolism
  • Neutralization Tests
  • Phenotype
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / pathology*
  • Receptors, Growth Factor / genetics
  • Receptors, Growth Factor / metabolism
  • Transforming Growth Factor beta1 / pharmacology*


  • Actins
  • Antibodies
  • Ccl12 protein, mouse
  • Chemokine CCL2
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-13
  • Monocyte Chemoattractant Proteins
  • Receptors, Growth Factor
  • Transforming Growth Factor beta1
  • Collagen