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The natural product phyllanthusmin C enhances IFN-? production by human NK cells through upregulation of TLR-mediated NF-?B signaling.

ABSTRACT: Natural products are a major source for cancer drug development. NK cells are a critical component of innate immunity with the capacity to destroy cancer cells, cancer-initiating cells, and clear viral infections. However, few reports describe a natural product that stimulates NK cell IFN-? production and unravel a mechanism of action. In this study, through screening, we found that a natural product, phyllanthusmin C (PL-C), alone enhanced IFN-? production by human NK cells. PL-C also synergized with IL-12, even at the low cytokine concentration of 0.1 ng/ml, and stimulated IFN-? production in both human CD56(bright) and CD56(dim) NK cell subsets. Mechanistically, TLR1 and/or TLR6 mediated PL-C's activation of the NF-?B p65 subunit that in turn bound to the proximal promoter of IFNG and subsequently resulted in increased IFN-? production in NK cells. However, IL-12 and IL-15Rs and their related STAT signaling pathways were not responsible for the enhanced IFN-? secretion by PL-C. PL-C induced little or no T cell IFN-? production or NK cell cytotoxicity. Collectively, we identify a natural product with the capacity to selectively enhance human NK cell IFN-? production. Given the role of IFN-? in immune surveillance, additional studies to understand the role of this natural product in prevention of cancer or infection in select populations are warranted.

SUBMITTER: Deng Y

PROVIDER: S-EPMC4162489 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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The natural product phyllanthusmin C enhances IFN-γ production by human NK cells through upregulation of TLR-mediated NF-κB signaling.

Deng Youcai Y Chu Jianhong J Ren Yulin Y Fan Zhijin Z Ji Xiaotian X Mundy-Bosse Bethany B Yuan Shunzong S Hughes Tiffany T Zhang Jianying J Cheema Baljash B Camardo Andrew T AT Xia Yong Y Wu Lai-Chu LC Wang Li-Shu LS He Xiaoming X Kinghorn A Douglas AD Li Xiaohui X Caligiuri Michael A MA Yu Jianhua J

Journal of immunology (Baltimore, Md. : 1950) 20140813 6

Natural products are a major source for cancer drug development. NK cells are a critical component of innate immunity with the capacity to destroy cancer cells, cancer-initiating cells, and clear viral infections. However, few reports describe a natural product that stimulates NK cell IFN-γ production and unravel a mechanism of action. In this study, through screening, we found that a natural product, phyllanthusmin C (PL-C), alone enhanced IFN-γ production by human NK cells. PL-C also synergize ...[more]

PMID: 25122922

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Project description:IntroductionToll-like receptor (TLR)4 promotes joint inflammation in mice. Despite that several studies report a functional link between TLR4 and interleukin-(IL-)1? in arthritis, TLR4-mediated regulation of the complicated cytokine network in arthritis is poorly understood. To address this, we investigated the mechanisms by which TLR4 regulates the cytokine network in antibody-induced arthritis.MethodsTo induce arthritis, we injected mice with K/BxN serum. TLR4-mediated pathogenesis in antibody-induced arthritis was explored by measuring joint inflammation, cytokine levels and histological alteration.ResultsCompared to wild type (WT) mice, TLR4-/- mice showed attenuated arthritis and low interferon (IFN)-?, IL-12p35 and IL-1? transcript levels in the joints, but high transforming growth factor (TGF)-? expression. Injection of lipopolysaccharide (LPS) enhanced arthritis and exaggerated joint cytokine alterations in WT, but not TLR4-/- or IL-12p35-/- mice. Moreover, STAT4 phosphorylation in joint cells and intracellular IL-12p35 expression in macrophages, mast cells and Gr-1+ cells were detected in WT mice with arthritis and enhanced by LPS injection. Therefore, IL-12p35 appears to act downstream of TLR4 in antibody-induced arthritis. TLR4-mediated IL-12 production enhanced IFN-? and IL-1? production via T-bet and pro-IL-1? production. Recombinant IL-12, IFN-? and IL-1? administration restored arthritis, but reduced joint TGF-? levels in TLR4-/- mice. Moreover, a TGF-? blockade restored arthritis in TLR4-/- mice. Adoptive transfer of TLR4-deficient macrophages and mast cells minimally altered joint inflammation and cytokine levels in macrophage- and mast cell-depleted WT mice, respectively, whereas transfer of WT macrophages or mast cells restored joint inflammation and cytokine expression. Gr-1+ cell-depleted splenocytes partially restored arthritis in TLR4-/- mice.ConclusionTLR4-mediated IL-12 production by joint macrophages, mast cells and Gr-1+ cells enhances IFN-? and IL-1? production, which suppresses TGF-? production, thereby promoting antibody-induced arthritis.

Dataset Information

The natural product phyllanthusmin C enhances IFN-? production by human NK cells through upregulation of TLR-mediated NF-?B signaling.

Publications

The natural product phyllanthusmin C enhances IFN-γ production by human NK cells through upregulation of TLR-mediated NF-κB signaling.

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