Macrophage-derived
insulin-like growth factor-I (
IGF-I) has long been implicated in the pathogenesis of the
interstitial lung disease,
idiopathic pulmonary fibrosis, in part, by its ability to 1) stimulate the proliferation and survival of fibroblasts and myofibroblasts and 2) promote
collagen matrix synthesis by these cells. However, little is known about the mechanisms that stimulate the expression of
IGF-I by macrophages. Previous studies have shown that the development of
pulmonary fibrosis is accompanied by enhanced expression of Th2-profile
cytokines, especially IL-4, and diminished expression of Th1
cytokines, including IFN-gamma. In addition, in vitro studies have shown that IFN-gamma down-regulates the expression of
IGF-I. Thus, the paucity of IFN-gamma in the fibrotic lung may favor increased
growth factor production by allowing Th2
cytokines to predominate. In view of these findings, we investigated the hypothesis that Th2
cytokines stimulate the expression of
IGF-I by macrophages. Incubation with IL-4 or
IL-13 led to concentration- and time-dependent increases in the expression of
IGF-I mRNA and the secretion of
IGF-I protein by mouse macrophages as a consequence of increased transcription of
IGF-I pre-mRNA. Exposure of macrophages to IL-4 in the presence of IFN-gamma inhibited the increase in the expression of
IGF-I. Studies using STAT6-deficient macrophages indicated that the increase in
IGF-I expression was dependent on STAT6. In addition, the down-regulation of
IGF-I expression by IFN-gamma was absent in STAT1-deficient macrophages. Collectively, these findings define a homeostatic mechanism in which Th2
cytokines promote, and Th1
cytokines inhibit, the expression of
IGF-I by macrophages.