Thrombomodulin RNA Is Destabilized Through Its 3′-Untranslated Element in Cells Exposed to IFN-γ

Angels Navarro, Mathias Frevel, Ana M. Gamero, Bryan R.G. Williams, Gerald Feldman, Andrew C. Larner

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11 Citations (Scopus)


Interferon-γ (IFN-γ) is a potent activator of mononuclear phagocytes, allowing them to play a prominent role in acute and chronic inflammatory responses. IFN-γ binding to its cell surface receptor initiates changes in the steady-state levels of cellular RNAs, permitting the proteins encoded by these RNAs to exert its biologic actions. Hundreds of cellular RNAs have been identified whose rates of transcription are altered by incubation of cells with IFNs. The rates of transcription of many of the genes encoding these RNAs are enhanced by IFN-γ-mediated activation of the Stat1 transcription factor that is tyrosine phosphorylated and translocates to the nucleus, where it binds enhancers present in IFN-stimulated genes (ISGs). IFN-γ can also modify the concentrations of some RNAs by posttranscriptional mechanisms. However, very little is understood about the molecular mechanisms regulating this phenomenon. We have identified the RNA encoding thrombomodulin (TM), a physiologic receptor for thrombin, that is downregulated in primary human monocytes incubated with IFN-γ. Using actinomycin D as a transcriptional inhibitor, we show that the mRNA half-life is rapidly shortened by IFN-γ. The TM transcript contains a large 3′-untranslated region (UTR), with several AU-rich elements (AREs), elements that have been implicated in the regulation of mRNA decay. Using a tetracycline-regulatory promoter system, we analyzed RNA levels in the absence of transcription of TM. Results from these experiments indicate that incubation of cells with IFN-γ accelerates the decay of TM RNA through its 3′-UTR. This is the first report describing a clear posttranscriptional downregulation of an mRNA by IFN-γ that identifies the 3′-UTR as a target of IFN-γ-stimulated destabilization.

Original languageEnglish
Pages (from-to)723-728
Number of pages6
JournalJournal of Interferon and Cytokine Research
Issue number12
Publication statusPublished - 1 Dec 2003
Externally publishedYes

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