title: Hypothemycin inhibits tumor necrosis factor-α production by tristetraprolin-dependent down-regulation of mRNA stability in lipopolysaccharide-stimulated macrophages.
abstract: Hypothemycin, a resorcylic acid lactone polyketide, has been shown to inhibit oncogenic ras-transformation and T cell activation. In the present study, we investigated the effect of hypothemycin on tumor necrosis factor-α (TNF-α) production in macrophages and the molecular mechanisms involved in this effect. Hypothemycin potently suppressed the TNF-α production without affecting nitric oxide production in lipopolysaccharide (LPS)-stimulated macrophages. However, hypothemycin had no effect on the activity of TNF-α-converting enzyme, a key enzyme for converting membrane-bound pro-TNF-α into soluble TNF-α. Further study demonstrated that the stability of TNF-α mRNA was decreased by hypothemycin treatment. In addition, hypothemycin suppressed LPS-induced phosphorylation of p38 MAPK and ERK. Moreover, knockdown of tristetraprolin (TTP), which is an important trans-acting regulator of TNF-α mRNA stability and downstream target of p38 MAPK and ERK, reversed hypothemycin-mediated inhibition of TNF-α mRNA expression. Collectively, our results suggest that hypothemycin suppresses TNF-α production by TTP-dependent destabilization of TNF-α mRNA and this is mediated, at least in part, by blocking the activation of p38 MAPK and ERK.
authors.affiliation: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk, 363-883, Republic of Korea.
authors.forename: Ki Hwan
authors.initials: KH
authors.lastname: Park
authors.affiliation: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk, 363-883, Republic of Korea.
authors.forename: Yeo Dae
authors.initials: YD
authors.lastname: Yoon
authors.affiliation: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk, 363-883, Republic of Korea.
authors.forename: Moo Rim
authors.initials: MR
authors.lastname: Kang
authors.affiliation: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk, 363-883, Republic of Korea.
authors.forename: Jieun
authors.initials: J
authors.lastname: Yun
authors.affiliation: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk, 363-883, Republic of Korea.
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Oh
authors.affiliation: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk, 363-883, Republic of Korea.
authors.forename: Chang Woo
authors.initials: CW
authors.lastname: Lee
authors.affiliation: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk, 363-883, Republic of Korea.
authors.forename: Myeong Youl
authors.initials: MY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk, 361-783, Republic of Korea.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk, 361-783, Republic of Korea.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk, 363-883, Republic of Korea. Electronic address: kanjon@kribb.re.kr.
authors.forename: Jong Soon
authors.initials: JS
authors.lastname: Kang
mesh_terms: D051722:ADAM Proteins / Q000187:drug effects / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D000067996:RAW 264.7 Cells; D020871:RNA Stability / Q000187:drug effects*; D051816:Tristetraprolin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015025:Zearalenone / Q000031:analogs & derivatives* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D008070:Lipopolysaccharides; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C120440:hypothemycin; D009569:Nitric Oxide; D015025:Zearalenone; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein
keywords: Hypothemycin; Tristetraprolin; Tumor necrosis factor-α; mRNA stability