Post-transcriptional control is another mechanism of IFN-y regulation that has been reported by a number of labs, although the precise mechanism by which this occurs remains to be defined. While mRNA stability in response to cytokine and other activation signals is p38 MAPK- and/or Stat4-dependent (Rao and Avni 2000; Ravindran et al. 2005; Rafaeli et al. 2002; Robertson 2005), a recent report provides evidence that mRNA stability observed upon IL-12 + IL-18 treatment of cells involves the 3' untranslated region of the ifng gene (Mavropoulos et al. 2005). In studies that offer a mechanistic insight into the mRNA stabilization process, it was demonstrated that the increase in IFN-y mRNA observed upon treatment of Jurkat cells with anti-LFAl and anti-CD3 was abrogated by treating the cells with siRNA to HuR, a protein that binds to the 3' untranslated portion of a number of cytokine mRNAs (Wang et al. 2006). Whether or not there is direct interaction of HuR with the IFN-y mRNA remains to be determined.
In preliminary studies, we (HAY) have found that deletion of the 100-bp region in the 3' UTR, which contains the AUUA repeats, results in significantly higher levels of expression of IFN-y in vivo when heterozygous mice are treated with interleukins 12 or 18 (H.A. Young, unpublished observations). While this result is consistent for a role for these elements in mRNA stabilization, proof of this model awaits further validation.
Thus, while IFN-y mRNA stabilization is a consequence of treatment of cells with numerous activation signals, exactly how the p38MAPK pathway is responsible for this effect and the role of known/unknown RNA-binding proteins in mediating mRNA stabilization remains a target of future study.
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