Abstract
Preeclampsia (PE) is a human pregnancy-specific syndrome with abnormal activation of cells from the innate immune system. The present study evaluated whether silibinin (SB) treatment of monocytes from preeclamptic women could modulate NLRP1 and NLRP3 inflammasomes as well as TLR4/NF-κB pathway activation. Peripheral blood monocytes from 20 preeclamptic and 20 normotensive (NT) pregnant women, as well as the THP-1 cell line, were cultured with or without monosodium urate (MSU) or SB. NLRP1, NLRP3, Caspase-1, TLR4, MyD88, NF-κB, IL-1β, IL-18, TNF-α and IL-10 gene expression by monocytes was analysed by quantitative real-time polymerase chain reaction (qPCR), while inflammatory cytokine production and p65NF-κB activity were determined by enzyme-linked immunosorbent assays (ELISAs). TLR4/MyD88/NF-κB and NLRP1/NLRP3 inflammasomes pathways in THP-1 cells were evaluated by flow cytometry and western blot respectively. Compared with NT women, monocytes from preeclamptic women showed The Ethics Committee of the Botucatu Medical School approved the study (protocol number 2.333.216)higher endogenous activation of NLRP1/NLRP3 inflammasomes and the TLR4/NF-κB pathway as well as higher gene and protein expression of IL-1β, IL-18 and TNF-α, and lower expression of IL-10. Monocyte stimulation with MSU increased inflammation-related genes as well as NF-κB activity. In vitro, SB treatment of monocytes from preeclamptic women reduced the basal activation of these cells by decreasing NLRP1/NLRP3 inflammasomes and p65NF-κB activity. THP-1 cells exhibited a similar immunological response profile to monocytes from preeclamptic women when cultured with or without MSU or SB. These results suggest uric acid participates in the systemic inflammatory response characteristic of preeclampsia and that in vitro SB treatment can modulate the sterile inflammation established in monocytes from preeclamptic women.
Highlights
Silymarin is a flavonoid complex extracted from the seeds and fruit of Silybum marianum, a milk thistle plant that belongs to the family Asteraceae
SB properties were demonstrated by dose-dependent inhibition of hydrogen peroxide (H2 O2 ) release as well as production of tumour necrosis factor alpha (TNF-α), interleukin-10 (IL-10), transforming growth factor beta (TGF-β) and prostaglandin E2 (PGE2) by peripheral blood monocytes from healthy individuals stimulated with lipopolysaccharide (LPS) [3,4]
We demonstrated that SB inhibits NF-κB pathway activation and pro-inflammatory cytokine production, including IL-1β and TNF-α, in peripheral blood mononuclear cells (PBMCs) from pregnant women with preeclampsia [14,23]
Summary
Silymarin is a flavonoid complex extracted from the seeds and fruit of Silybum marianum, a milk thistle plant that belongs to the family Asteraceae. It is one of the oldest medicinal herbs, and it is used as anti-inflammatory and hepatoprotective agent [1,2]. Molecules 2019, 24, 1548 active component of silymarin and presents anti-inflammatory, hepatoprotective, anti-fibrotic, anticarcinogenic, antioxidant and immunomodulatory activities. The SB anti-inflammatory effects are attributed to its suppression of nuclear factor kappa-B (NF-κB)-regulated gene products [3,5,6]. NF-κB plays a role in the pathogenesis of inflammation, a fact that suggests that NF-κB pathway inhibitors might be effective targets for treatment of chronic inflammatory diseases [6]
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