Pro- and Anti-inflammatory Cytokines Regulate Insulin-like Growth Factor Binding Protein Production by Fetal Rat Lung Fibroblasts

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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 β or tumor necrosis factor (TNF)- α for 48 h demonstrated increased abundance of CM IGFBP-3 (5.9- and 4.7-fold increases for IL-1 β and TNF- α, respectively) and IGFBP-4 (5.7- and 7.4-fold increases for IL-1 β and TNF- α, 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 β, or TNF- α 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 β or TNF- α 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.

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