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Hypothemycin Inhibits Tumor Necrosis factor-α Production by Tristetraprolin-Dependent Down-Regulation of mRNA Stability in Lipopolysaccharide-Stimulated Macrophages

Hypothemycin Inhibits Tumor Necrosis factor-α Production by Tristetraprolin-Dependent Down-Regulation of mRNA Stability in Lipopolysaccharide-Stimulated Macrophages

Ki Hwan Park, Yeo Dae Yoon, Moo Rim Kang, Jieun Yun, Soo Jin Oh, Chang Woo Lee, Myeong Youl Lee, Sang-Bae Han, Youngsoo Kim, Jong Soon Kang

Int Immunopharmacol. 2015 Dec;29(2):863-868.

PMID: 26371861

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP76958673	Hypothemycin		76958-67-3	Price

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