Post-transcriptional regulation of tumour necrosis factor alpha production (original) (raw)

2000, Annals of the Rheumatic Diseases

Tumour necrosis factor (TNF) is a proinflammatory cytokine produced by activated macrophages, lymphocytes and other cells. 1-3 The production of TNF is under transcriptional and post-transcriptional control. 4-10 Post-transcriptional control of TNF 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 TNF transcripts 11-13 is an important determinant of posttranscriptional 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, TNF , GM-CSF) possess AUrich 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 suYcient to promote the degradation of transcripts encoding immediate early proteins, both class I and class II AREs regulate the production of cytokines such as TNF , GM-CSF, interleukin 3 (IL3) and interferon (IFN). The 3' untranslated region of TNF 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 TIA-1 and TIAR. 14 The complex assembled on the class I ARE (designated complex 2) includes an unidentified 55 kDa protein. Whereas complex 1 forms with extracts derived from activated and unactivated macrophages, complex 2 is only formed using extracts derived from activated macrophages. The importance of the TNF ARE is underscored by the severe phenotype of transgenic knock-in mice expressing TNF transcripts that lack the ARE. 16 17 Overexpression of TNF by these animals results in chronic inflammatory arthritis and inflammatory bowel disease. The overexpression of TNF is a consequence of increased transcript stability combined with