Interferon-gamma inhibits macrophage insulin-like growth factor-I synthesis at the transcriptional level
| Autor: | Arya Biragyn, Natalie Rebeiz, Keith W. Kelley, D. L. Brunke-Reese, Sean Arkins |
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| Rok vydání: | 1995 |
| Předmět: |
Male
Macrophage colony-stimulating factor Transcription Genetic medicine.medical_treatment Rats Inbred WF Cycloheximide Biology Interferon-gamma Mice chemistry.chemical_compound Endocrinology Protein biosynthesis medicine Animals Macrophage Interferon gamma RNA Messenger Insulin-Like Growth Factor I Molecular Biology Immunosorbent Techniques Cell Line Transformed Mice Inbred BALB C Messenger RNA Macrophage Colony-Stimulating Factor Macrophages Growth factor General Medicine Molecular biology Recombinant Proteins Rats Cytokine chemistry Female medicine.drug |
| Zdroj: | Molecular Endocrinology. 9:350-360 |
| ISSN: | 1944-9917 0888-8809 |
| DOI: | 10.1210/mend.9.3.7776981 |
| Popis: | Spontaneous production of insulin-like growth factor-I (IGF-I) by inflammatory macrophages contributes to aberrant wound healing, but little is known about regulation of IGF-I synthesis in myeloid cells. The T cell-derived cytokine interferon-gamma (IFN gamma) inhibits several fibrogenic and angiogenic components of the wound-healing response. We have used metabolic labeling of primary colony stimulating factor-1 (CSF-1)-derived macrophages and a transformed macrophage cell line (PU5-1R) followed by immunoprecipitation to demonstrate that synthesis of the 17 kilodalton (kDa) prepro-IGF-I protein by these cells is substantially inhibited by IFN gamma. An exon 4 IGF-I/beta-actin riboprobe expression cassette was used in RNase protection assays to show that IFN gamma also reduces steady state levels of IGF-I mRNA in three different populations of macrophages in a time- and dose-dependent manner. This effect is specific for IFN gamma because neither the IFNs-alpha/beta nor lipopolysaccharide (LPS) affects expression of steady state IGF-I transcripts. Down-regulation of IGF-I mRNA by IFN gamma is dependent on de novo protein synthesis and is abrogated by coculture with cycloheximide. Nuclear run-on assays revealed that elongation of IGF-I transcripts is absent in fresh bone marrow cells but is induced several-fold after cells are cultured for 6 days with CSF-1. Treatment of these CSF-1-derived macrophages with IFN gamma for 6 h substantially inhibits synthesis of IGF-I mRNA. Studies on the decay of IGF-I mRNA in PU5-1R macrophages treated with an RNA polymerase inhibitor confirmed that the decline in IGF-I steady state mRNA in IFN gamma-treated cultures arises from an inhibition of transcription rather than from a reduction in mRNA stability. Since a variety of inflammatory mediators can induce expression of IGF-I in macrophages, inhibition of macrophage IGF-I synthesis by IFN gamma provides a mechanism by which leukocytes regulate levels of this growth factor in their microenvironment. |
| Databáze: | OpenAIRE |
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