Am. J. Respir. Cell Mol. Biol.,
Volume 26, Number 3, March, 2002 283-289
Pro- and Anti-inflammatory Cytokines Regulate Insulin-like Growth Factor
Binding Protein Production by Fetal Rat Lung Fibroblasts
Wayne A.
Price,
Billie M.
Moats-Staats,
and
Alan D.
Stiles
Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
The inflammatory response of the lung to noxious factors contributes to the pathogenesis of chronic lung injury. Inflammatory mediators regulate the insulin-like growth factor (IGF)
system, a key modulator of lung fibroblast proliferation. The
activity of IGFs is regulated by IGF-binding proteins (IGFBPs)
secreted by lung cells. To investigate the regulation of lung fibroblast IGFBPs by cytokines, we exposed 19-d fetal rat lung
fibroblasts to various pro- and anti-inflammatory mediators.
IGFBP abundance in conditioned medium (CM) was measured
by ligand blot and RNA transcript abundance by RNase protection assays. Fetal rat lung fibroblasts exposed to interleukin
(IL)-1
or tumor necrosis factor (TNF)-
for 48 h demonstrated increased abundance of CM IGFBP-3 (5.9- and 4.7-fold
increases for IL-1 and TNF-, respectively) and IGFBP-4 (5.7- and 7.4-fold increases for IL-1 and TNF-, respectively) that
was accompanied by a small increase in IGFBP-4 mRNA and a
larger increase in IGFBP-3 mRNA abundance. IGFBP-4 specific
proteolysis was examined in CM collected from fetal rat lung
fibroblasts after incubation with serum-free medium (SFM), IL-1, or TNF- for 48 h. Cell-free aliquots of SFM-CM incubated at 37°C for 24 h showed a 65% decrease in IGFBP-4
abundance that was inhibited by 1,10-phenanthroline. In contrast, CM from cells exposed to IL-1 or TNF- incubated at
37°C for 24 h did not show a significant decrease in IGFBP-4
abundance unless IGF-I was present during the cell-free incubation. Addition of IGFBP-3 to aliquots of SFM-CM reversed
the IGF-I-mediated acceleration of IGFBP-4 proteolysis. Similarly, addition of IGFBP-3 to cells in culture increased the accumulation of CM IGFBP-4. These results demonstrate that cytokines regulate IGFBP production and clearance by fetal lung
cells and suggest a mechanism by which cytokines regulate cell proliferation following lung injury.
Abbreviations: acute respiratory distress syndrome, ARDS; conditioned
medium, CM; calf serum, CS; insulin-like growth factor, IGF; IGF-binding
protein, IGFBP; type 1 IGF receptor, IGF-1R; interleukin, IL; serum-free
medium, SFM; tumor necrosis factor-, TNF-.
