TGF-β Decreases the Stability of IL-18-Induced IFN-γ mRNA through the Expression of TGF-β-Induced Tristetraprolin in KG-1 Cells

We have previously reported that transforming growth factor-beta (TGF-beta) down-regulates interferon-gamma (IFN-gamma) production in an interleukin-18 (IL-18) treated mouse natural killer (NK) cell line, LNK5E6. In LNK5E6 cells, TGF-beta exhibited no inhibition of the IL-18-induced transcription of IFN-gamma, but did stimulate the degradation of IFN-gamma mRNA induced by IL-18. In the present study, we investigated the mechanism of the down-regulatory effects of TGF-beta on IFN-gamma mRNA expression in a human myelomonocytic cell line, KG-1, which produces IFN-gamma in response to IL-18 alone. Interestingly, IL-18 induced the production of the IFN-gamma through the stabilization of IFN-gamma mRNA, but not the enhanced transcription of IFN-gamma gene. The stability of IFN-gamma mRNA was regulated by mRNA destabilizing elements in the 3'untranslated region (UTR) of IFN-gamma mRNA, especially adenylate-uridylate (AU)-rich elements (AREs) in the 5' half of 3'UTR. Tristetraprolin (TTP), one of the ARE-binding proteins, destabilizes IFN-gamma mRNA, and IL-18 repressed the expression of TTP mRNA. Moreover, TGF-beta repressed the IL-18-induced expression of IFN-gamma mRNA through the induction of TTP mRNA to destabilize IFN-gamma mRNA. Our data is the first to reveal that the crosstalk between IL-18 and TGF-beta through the expression of TTP regulates the production of IFN-gamma.