title: TGF-β decreases the stability of IL-18-induced IFN-γ mRNA through the expression of TGF-β-induced tristetraprolin in KG-1 cells.
abstract: 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.
authors.affiliation: Department of Drug Metabolism and Disposition, Graduate School of Pharmaceutical Sciences, Nagoya City University.
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Kenji
authors.initials: K
authors.lastname: Abe
authors.forename: Kikuo
authors.initials: K
authors.lastname: Onozaki
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Hayashi
mesh_terms: D002460:Cell Line; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics*; D020382:Interleukin-18 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051816:Tristetraprolin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020382:Interleukin-18; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D051816:Tristetraprolin; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases