Alveolar macrophages stimulated with titanium dioxide, chrysotile asbestos, and residual oil fly ash upregulate the PDGF receptor-alpha on lung fibroblasts through an IL-1beta-dependent mechanism

Am J Respir Cell Mol Biol. 1997 Mar;16(3):283-92. doi: 10.1165/ajrcmb.16.3.9070613.


Enhanced proliferation of fibroblasts is a primary characteristic of lung fibrosis. Macrophage-secreted platelet-derived growth factor (PDGF) is a potent mitogen and chemoattractant for lung fibroblasts. The magnitude of the fibroblast PDGF response is dependent on the number of PDGF receptor alpha (PDGF-R alpha) relative to PDGF-R beta at the cell surface. We recently reported that upregulation of the PDGF-R alpha subtype by interleukin (IL)-1beta results in enhanced lung fibroblast proliferation in response to PDGF-AA, PDGF-AB, and PDGF-BB whereas transforming growth factor (TGF)-beta1 has the opposite effect. Both IL-1beta and TGF-beta1 are produced by particle-activated macrophages in vivo and in vitro. We studied the net effect of macrophage conditioned medium (MOCM), which contains both IL-1beta and TGF-beta1, on the expression of the lung fibroblast PDGF receptor system. MOCM obtained from unstimulated, titanium dioxide (TiO2)-, chrysotile asbestos-, or residual oil fly ash (ROFA)-exposed macrophages in vitro increased [125I]PDGF-AA binding 3-, 6-, 6-, and 20-fold, respectively. These increases correlated with increased PDGF-R alpha mRNA and protein expression as shown by northern and western assays. PDGF-AB and -BB-stimulated [3H]thymidine incorporation by fibroblasts was enhanced 5-, 5-, 10-, and 20-fold by pretreatment with MOCM from unstimulated, TiO2-, asbestos-, and ROFA-exposed macrophages, respectively. [125I]PDGF-AA binding experiments using the IL-1 receptor antagonist blocked the upregulatory effect of all MOCM samples. Latent TGF-beta1 present in MOCM was activated by acid treatment, inhibiting upregulation by approximately 60%, a result similar to experiments with IL-1beta and TGF-beta1 mixtures. Treatment with a TGF-beta neutralizing antibody restored full upregulatory activity to acidified MOCM. Thus activated macrophages increase lung fibroblast PDGF-R alpha primarily due to the secretion of IL-1beta. Intratracheal instillation of ROFA particles in rats induced a 2-fold increase in total lung PDGF-R alpha mRNA in vivo. These findings support the idea that macrophage-derived IL-1beta plays a key role in the initiation of a fibrotic response by increasing fibroblast PDGF-R alpha expression, thereby dramatically potentiating the mitogenic response to PDGF.

MeSH terms

  • Animals
  • Asbestos, Serpentine / pharmacology*
  • Carbon / pharmacology*
  • Cell Division
  • Cells, Cultured
  • Coal Ash
  • Culture Media, Conditioned
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Hydrochloric Acid / pharmacology
  • Interleukin-1 / physiology*
  • Lung / cytology
  • Lung / metabolism*
  • Macrophages, Alveolar / drug effects
  • Macrophages, Alveolar / physiology*
  • Male
  • Particulate Matter
  • Platelet-Derived Growth Factor / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Platelet-Derived Growth Factor alpha
  • Receptors, Interleukin-1 / antagonists & inhibitors
  • Receptors, Platelet-Derived Growth Factor / biosynthesis
  • Receptors, Platelet-Derived Growth Factor / genetics
  • Titanium / pharmacology*
  • Transforming Growth Factor beta / physiology
  • Up-Regulation / drug effects*


  • Asbestos, Serpentine
  • Coal Ash
  • Culture Media, Conditioned
  • Interleukin-1
  • Particulate Matter
  • Platelet-Derived Growth Factor
  • Receptors, Interleukin-1
  • Transforming Growth Factor beta
  • platelet-derived growth factor A
  • titanium dioxide
  • Carbon
  • Titanium
  • Receptor, Platelet-Derived Growth Factor alpha
  • Receptors, Platelet-Derived Growth Factor
  • Hydrochloric Acid