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Post-transcriptional regulation of tumour necrosis factor α production
  1. Paul Anderson
  1. Division of Rheumatology and Immunology, Brigham and Women's Hospital, Smith 652, One Jimmy Fund Way, Boston, MA 02115, USA
  1. Dr Anderson (panderson{at}rics.bwh.harvard.edu)

https://doi.org/10.1136/ard.59.suppl_1.i3

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    Tumour necrosis factor α (TNFα) is a proinflammatory cytokine produced by activated macrophages, lymphocytes and other cells.1-3 The production of TNFα is under transcriptional and post-transcriptional control.4-10Post-transcriptional control of TNFα expression is achieved by regulating translational initiation, mRNA stability, and polyadenylation.6 ,7 ,10 An adenine and uridine (AU)-rich element (ARE) in the 3' untranslated region (3' UTR) of TNFα transcripts11-13 is an important determinant of post-transcriptional control. Transfer of this element to heterologous reporter transcripts changes the expression of the reporter protein. Transacting factors that bind to the ARE and participate in post-transcriptional control have recently been identified. The ARE binding proteins expressed in a given cell are thought to determine the level of protein expression.

    AU-rich elements (AREs)

    The 3' untranslated region of mRNAs encoding short lived immediate early genes (for example, fos, jun) as well as selected cytokines (for example, TNFα, GM-CSF) possess AU-rich elements that regulate protein expression. Class I AREs consist of one or more pentamer repeats (that is, AUUUA), whereas class II AREs consist of one or more nonamer repeats (that is, AUUUAUUUA). Whereas class I AREs are sufficient to promote the degradation of transcripts encoding immediate early proteins, both class I and class II AREs regulate the production of cytokines such as TNFα, GM-CSF, interleukin 3 (IL3) and interferon α (IFNα). The 3' untranslated region of TNFα transcripts contains both class I and class II AREs. Electrophoretic mobility shift assays have identified two distinct regulatory complexes that assemble on these adjacent cis elements in HeLa cells.14 ,15 The complex assembled on the class II ARE (designated complex 1) includes the related RNA binding proteins …

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