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Silymarin suppresses basal and stimulus-induced activation, exhaustion, differentiation, and inflammatory markers in primary human immune cells.

ABSTRACT: Silymarin (SM), and its flavonolignan components, alter cellular metabolism and inhibit inflammatory status in human liver and T cell lines. In this study, we hypothesized that SM suppresses both acute and chronic immune activation (CIA), including in the context of HIV infection. SM treatment suppressed the expression of T cell activation and exhaustion markers on CD4+ and CD8+ T cells from chronically-infected, HIV-positive subjects. SM also showed a trend towards modifying CD4+ T cell memory subsets from HIV+ subjects. In the HIV-negative setting, SM treatment showed trends towards suppressing pro-inflammatory cytokines from non-activated and pathogen-associated molecular pattern (PAMP)-activated primary human monocytes, and non-activated and cytokine- and T cell receptor (TCR)-activated mucosal-associated invariant T (MAIT) cells. The data suggest that SM elicits broad anti-inflammatory and immunoregulatory activity in primary human immune cells. By using novel compounds to alter cellular inflammatory status, it may be possible to regulate inflammation in both non-disease and disease states.

SUBMITTER: Lovelace ES

PROVIDER: S-EPMC5291532 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Silymarin suppresses basal and stimulus-induced activation, exhaustion, differentiation, and inflammatory markers in primary human immune cells.

Lovelace Erica S ES Maurice Nicholas J NJ Miller Hannah W HW Slichter Chloe K CK Harrington Robert R Magaret Amalia A Prlic Martin M De Rosa Stephen S Polyak Stephen J SJ

PloS one 20170203 2

Silymarin (SM), and its flavonolignan components, alter cellular metabolism and inhibit inflammatory status in human liver and T cell lines. In this study, we hypothesized that SM suppresses both acute and chronic immune activation (CIA), including in the context of HIV infection. SM treatment suppressed the expression of T cell activation and exhaustion markers on CD4+ and CD8+ T cells from chronically-infected, HIV-positive subjects. SM also showed a trend towards modifying CD4+ T cell memory ...[more]

PMID: 28158203

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Project description:BackgroundTreated HIV infection is associated with heightened inflammation which can contribute to increased risk of cardiovascular disease (CVD). We have previously shown that anisocytosis, as measured by red cell distribution width (RDW), is independently associated with prevalent CVD in people living with HIV (PLHIV). In this study, we sought to identify immune correlates of RDW in PLHIV receiving antiretroviral therapy.MethodsWe performed a cross-sectional and longitudinal analysis of 147 virally-suppressed PLHIV, who had LDL < 130 mg/dL and evidence of heightened inflammation, in a randomized trial of statin therapy. A complete blood count and biomarkers of inflammation and immune activation/exhaustion were measured in peripheral blood at entry and after 24 and 48 weeks. Associations with RDW were estimated using linear regression and linear mixed models.ResultsThe median age (IQR) for the cohort at enrollment was 46 (40-53) years; 78% were male and 68% were African American. The median RDW for the cohort was 13.4% (12.9-14.0). Compared with the lowest RDW tertile, patients in the highest tertile were less likely to be male, and more likely to be African American, have lower hemoglobin, lower mean corpuscular volume, and higher platelet counts (all P < 0.05). At baseline, RDW weakly correlated with C-reactive protein (r = 0.196), d-dimer (r = 0.214), fibrinogen (r = 0.192), IL-6 (r = 0.257), CD4+DR+38+ T cells (r = 0.195), and CD4+PD1+ T cells (r = 0.227), all P < 0.05. Only IL-6, CD4+38+DR+ T cells, and CD4+PD1+ T_cells remained associated after adjustment for clinical factors known to affect RDW in the general population. Over 48 weeks, RDW did not change and there was no significant effect of statin (P = 0.45). After adjustment for clinical parameters, RDW remained positively associated with CD4+38+DR+ and CD4+PD1+ T cells across all time points (P = 0.05).ConclusionIn this population of treated HIV+ subjects, anisocytosis was associated with biomarkers of inflammation and T-cell activation/exhaustion over time and independent of clinical confounders. Therefore, RDW may be a useful prognostic biomarker of cardiovascular risk that partially reflects chronic inflammation and immune exhaustion in PLHIV receiving antiretroviral therapy.

Project description:Inflammatory responses and osteoclast differentiation play pivotal roles in the pathogenesis of osteolytic bone diseases such as periodontitis. Although overexpression or inhibition of peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1) offers a possible therapeutic strategy for chronic inflammatory diseases, the role of PIN1 in periodontal disease is unclear. The aim of the present study was to evaluate PIN1 expression in periodontitis patients as well as the effects of PIN1 inhibition by juglone or PIN1 small-interfering RNA (siRNA) and of PIN1 overexpression using a recombinant adenovirus encoding PIN1 (Ad-PIN1) on the inflammatory response and osteoclastic differentiation in lipopolysaccharide (LPS)- and nicotine-stimulated human periodontal ligament cells (PDLCs). PIN1 was up-regulated in chronically inflamed PDLCs from periodontitis patients and in LPS- and nicotine-exposed PDLCs. Inhibition of PIN1 by juglone or knockdown of PIN1 gene expression by siRNA markedly attenuated LPS- and nicotine-stimulated prostaglandin E2 (PGE2) and nitric oxide (NO) production, as well as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, whereas PIN1 overexpression by Ad-PIN1 increased it. LPS- and nicotine-induced nuclear factor (NF)-κB activation was blocked by juglone and PIN1 siRNA but increased by Ad-PIN1. Conditioned medium prepared from LPS- and nicotine-treated PDLCs increased the number of tartrate-resistant acid phosphatase-stained osteoclasts and osteoclast-specific gene expression. These responses were blocked by PIN1 inhibition and silencing but stimulated by Ad-PIN1. Furthermore, juglone and PIN1 siRNA inhibited LPS- and nicotine-induced osteoclastogenic cytokine expression in PDLCs. This study is the first to demonstrate that PIN1 inhibition exhibits anti-inflammatory effects and blocks osteoclastic differentiation in LPS- and nicotine-treated PDLCs. PIN1 inhibition may be a therapeutic strategy for inflammatory osteolysis in periodontal disease.

Dataset Information

Silymarin suppresses basal and stimulus-induced activation, exhaustion, differentiation, and inflammatory markers in primary human immune cells.

Publications

Silymarin suppresses basal and stimulus-induced activation, exhaustion, differentiation, and inflammatory markers in primary human immune cells.

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