Induction of macrophage insulin-like growth factor-I expression by the Th2 cytokines IL-4 and IL-13
Open accessAbstract
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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Igf1 expression is inhibited by pro-inflammatory stimuli and enhanced in anti-inflammatory environments.
“Our findings, in line with previous studies (59,68–71), show that Igf1 expression is inhibited by pro-inflammatory stimuli and enhanced in anti-inflammatory environments.”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [70]
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“It has also been suggested in macrophages that STAT6 is essential for IL4-mediated up-regulation of Igf1 expression (Wynes and Riches 2003).”
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- Authors
- Wynes, M. W., & Riches, D. W. H.
- Affiliations
- National Jewish Health (US)
- ORCID
- Riches, David W H
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2003-10-01
- Volume
- 171
- Issue
- 7
- Pages
- 3550-3559
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2125584590
- Cited by
- 105
- References
- 64
- Citations by year
- 2026: 1 · 2024: 3 · 2023: 1 · 2021: 2 · 2020: 6 · 2019: 5 · 2018: 9 · 2017: 5 · 2016: 5 · 2015: 7 · 2014: 9 · 2013: 8 · 2012: 2
- FWCI
- 3.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p50hl056556-05, AI00048)
- National Heart, Lung, and Blood Institute (HL 55549, R01HL065326, HL 56556, R01HL055549, R01HL068628, HL-68628, HL-65326)
- National Institute of Allergy and Infectious Diseases (T32-AI00048, T32AI000048)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- insulin-like growth factor I, macrophages, Th2 cytokines, IL-4, IL-13, interferon-gamma, STAT6, STAT1, idiopathic pulmonary fibrosis, interstitial lung disease, Th1/Th2 balance
- MeSH terms
- Animals, Cells, Cultured, DNA-Binding Proteins, Drug Synergism, Gene Expression Regulation, Insulin-Like Growth Factor I, Interferon-gamma, Macrophages, Mice, Inbred BALB C, Mice, Inbred C3H, Transcription, Genetic, Signal Transduction, Trans-Activators, Interleukin-4, Mice, Knockout, Th2 Cells, Interleukin-13, STAT1 Transcription Factor, STAT6 Transcription Factor, Mice
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