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Am J Physiol Lung Cell Mol Physiol 278: L545-L551, 2000;
1040-0605/00 $5.00
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Vol. 278, Issue 3, L545-L551, March 2000

IGFBP-3 mediates TGF-beta 1-induced cell growth in human airway smooth muscle cells

Pinchas Cohen1, Roopmathy Rajah1, Joel Rosenbloom2, and David J. Herrick2

1 Department of Pediatrics, Mattel Children's Hospital at University of California, Los Angeles, California 90095-1752; and 2 Department of Anatomy, University of Pennsylvania, Children's Hospital, Philadelphia, Pennsylvania 19104

Both insulin-like growth factor binding protein-3 (IGFBP-3) and transforming growth factor-beta (TGF-beta ) have been separately shown to have cell-specific growth-inhibiting or growth-potentiating effects. TGF-beta stimulates IGFBP-3 mRNA and peptide expression in several cell types, and TGF-beta -induced growth inhibition and apoptosis have been shown to be mediated through the induction of IGFBP-3. However, a link between the growth stimulatory effects of TGF-beta and IGFBP-3-induction has not been shown. In this study, we investigated the role of IGFBP-3 in mediating TGF-beta 1-induced cell growth using human airway smooth muscle (ASM) cells as our model. TGF-beta 1 (1 ng/ml) treatment induced a 10- to 20-fold increase in the levels of expression of IGFBP-3 mRNA and protein. Addition of either IGFBP-3 or TGF-beta 1 to the growth medium resulted in an approximately twofold increase in cell proliferation. Coincubation of ASM cells with IGFBP-3 antisense (but not sense) oligomers as well as with an IGFBP-3 neutralizing antibody (but not with control IgG) blocked the growth induced by TGF-beta 1 (P < 0.001). Several IGFBP-3-associated proteins were observed in ASM cell lysates, which may have a role in the cellular responses to IGFBP-3. These findings demonstrate that IGFBP-3 is capable of mediating the growth stimulatory effect of TGF-beta in ASM cells.

insulin-like growth factor binding protein; cell proliferation; receptor; transforming growth factor.


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