Interferon-gamma- and phorbol myristate acetate-responsive elements involved in intercellular adhesion molecule-1 mRNA stabilization.

Treatment of cells with interferon (IFN)-gamma or phorbol myristate acetate (PMA) induces up-regulation of the level of intercellular adhesion molecule-1 (ICAM-1; CD54) mRNA by stabilization of an otherwise labile mRNA. Here, we have generated various deletion mutants of ICAM-1 and stably transfected them into the murine fibroblast Ltk- cells that express no endogenous ICAM-1 or -2 (CD102) in an effort to define the regions within ICAM-1 mRNA responsive to IFN-gamma or PMA. Induction of ICAM-1 mRNA in the transfected L cells by the treatment with IFN-gamma revealed that the truncation of the region of ICAM-1 mRNA encoding the cytoplasmic domain made it non-responsive to IFN-gamma whereas all other regions were dispensable. In contrast, PMA-induced accumulation of ICAM-1 mRNA required the 3'-untranslated region (UTR). To further elucidate the role of these regions in mRNA destabilization and responsiveness to IFN-gamma and PMA, ICAM-2 mRNA that is stable and not responsive to IFN-gamma or PMA was used as a reporter gene. The putative IFN-gamma-responsive region of ICAM-1 mRNA encoding its cytoplasmic domain rendered it unstable and responsive to IFN-gamma but not PMA. Conversely, the 3'-UTR of ICAM-1 fused with ICAM-2 mRNA also made it unstable and responsive to PMA but not IFN-gamma. Half-life analysis showed that the induction of these chimeric mRNAs by IFN-gamma and PMA was due, at least in part, to the prolongation of their turnover rate. These results taken together demonstrate that two distinct regions of ICAM-1 mRNA regulate its stability, one encoding the cytoplasmic domain and responsive to IFN-gamma and the other in the 3'-UTR and responsive to PMA.