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.
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.
Lindroos
P M
PM
Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Coin
P G
PG
Badgett
A
A
Morgan
D L
DL
Bonner
J C
JC
D000818:Animals; D017632:Asbestos, Serpentine / Q000494:pharmacology*; D002244:Carbon / Q000494:pharmacology*; D002455:Cell Division; D002478:Cells, Cultured; D060729:Coal Ash; D017077:Culture Media, Conditioned; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006851:Hydrochloric Acid / Q000494:pharmacology; D007375:Interleukin-1 / Q000502:physiology*; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000502:physiology*; D008297:Male; D052638:Particulate Matter; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020796:Receptor, Platelet-Derived Growth Factor alpha; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D017479:Receptors, Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000235:genetics; D014025:Titanium / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects*
D017632:Asbestos, Serpentine; D060729:Coal Ash; D017077:Culture Media, Conditioned; D007375:Interleukin-1; D052638:Particulate Matter; D010982:Platelet-Derived Growth Factor; D017472:Receptors, Interleukin-1; D016212:Transforming Growth Factor beta; C075278:platelet-derived growth factor A; C009495:titanium dioxide; D002244:Carbon; D014025:Titanium; D020796:Receptor, Platelet-Derived Growth Factor alpha; D017479:Receptors, Platelet-Derived Growth Factor; D006851:Hydrochloric Acid