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The Journal of Immunology, 2003, 171: 3550-3559.
Copyright © 2003 by The American Association of Immunologists

Induction of Macrophage Insulin-Like Growth Factor-I Expression by the Th2 Cytokines IL-4 and IL-131

Murry W. Wynes*,{dagger} and David W. H. Riches2,*,{dagger},{ddagger}

* Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206; and {dagger} Department of Immunology and {ddagger} Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262

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.




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