Interferon-γ inhibits macrophage insulin-like growth factor-I synthesis at the transcriptional level

Sean Arkins, Natalie Rebeiz, Deborah L. Brunke-Reese, Arya Biragyn, Keith W. Kelley

Research output: Contribution to journalArticlepeer-review

Abstract

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-γ (IFNγ) 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 IFNγ. An exon 4 IGF-I/β-actin riboprobe expression cassette was used in RNase protection assays to show that IFNγ 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 IFNγ because neither the IFNs- α/β nor lipopolysaccharide (LPS) affects expression of steady state IGF-I transcripts. Down-regulation of IGF-I mRNA by IFNγ 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 IFNγ 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 IFNγ- 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 IFNγ provides a mechanism by which leukocytes regulate levels of this growth factor in their microenvironment.

Original languageEnglish
Pages (from-to)350-360
Number of pages11
JournalMolecular Endocrinology
Volume9
Issue number3
DOIs
Publication statusPublished - Mar 1995
Externally publishedYes

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