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