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Preeclampsia (PE) is a multifactorial disease that is characterized by inflammation. Some of the factors responsible for this inflammation are the cells of the innate and adaptive immune systems and their interactions. The use of natural products, such as silibinin (SB), can contribute to the control of this inflammation and gestational success. The present study evaluated whether the flavonoid SB has an in vitro immunomodulatory effect on the signal transducers and transcription activators (STATs) signaling pathway and transcription factors of CD4 + T cell subsets obtained from preeclamptic and normotensive (NT) pregnant women. Peripheral blood mononuclear cells (PBMCs) from 18 preeclamptic and 18 NT pregnant women were cultured with and without SB to analyze the expression of STATs and transcription factors by flow cytometry, and cytokines were measured in the culture supernatant by ELISA. The results showed that treating cells with SB decreased STAT1/ STAT4/T-bet and STAT3/RORγt, which characteristic of Th1 and Th17 inflammatory profiles, as well as increased STAT6/GATA-3 and STAT5/FoxP3 of anti-inflammatory and regulatory profiles, respectively. In addition, PBMCs from preeclamptic women treated with SB released lower concentrations of inflammatory cytokines and higher levels of IL-10 and TGF-β. Therefore, SB plays an immunomodulatory role on CD4 + T cell subsets in PE, leading to the downregulation of inflammatory profiles and upregulation of anti-inflammatory and regulatory profiles. More studies are necessary to better understand the modulation of CD4 + T cell subsets by the JAK/STAT and NF-κB pathways in this gestational pathology., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Preeclampsia (PE) is a pregnancy-specific syndrome featuring intense activation of circulating monocytes and an imbalance between pro- and anti-inflammatory cytokines. The present study evaluated the immunomodulatory effect of silibinin (Sb) on the expression of surface markers and the nuclear transcription factor NF-κB signalling pathway of monocytes from preeclamptic women. Monocytes were cultured with or without Sb, and the mean fluorescence intensity of the surface molecules TLR4, CD64, and CD163 as well as the intracellular transcription factors IκB-α and NF-κBp65 was analysed by flow cytometry. The concentration of cytokines in the monocyte culture supernatant was determined by cytometric bead array and ELISA immunoassay. The results showed that the in vitro treatment of monocytes from preeclamptic women with Sb downregulated the endogenous activation of NF-κB and the expression of surface receptors TLR4 and CD64, and reduced the synthesis of the pro-inflammatory cytokines interleukin 1 (IL-1β), IL-6, IL-8, IL-12p70, IL-23, and tumour necrosis factor alpha (TNF-α) compared with cultures not treated with Sb. The presence of this flavonoid in monocyte cultures increased the expression of CD163 and IκBα and the release of IL-10 and transforming growth factor beta (TGF-β) in the culture supernatants, polarising these cells from the M1-like profile to the M2-like profile. The anti-inflammatory activity of Sb on the NF-κB activation pathway and induction of cell polarisation to the M2 profile was confirmed by an in vitro assay using monocytes from healthy, non-pregnant women. Treatment of monocytes from preeclamptic women with Sb polarises the cells to the M2-like phenotype, suggesting that this flavonoid has an immunomodulatory effect on the sterile inflammation characteristic of PE., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Autophagy is an important mechanism for tumor escape, allowing tumor cells to recover from the damage induced by chemotherapy, radiation therapy, and immunotherapy and contributing to the development of resistance. The pharmacological inhibition of autophagy contributes to increase the efficacy of antineoplastic agents. Exposing tumor cells to low concentrations of select autophagy-inducing antineoplastic agents increases their immunogenicity and enhances their ability to stimulate dendritic cell (DC) maturation. We tested whether the application of an autophagy-inhibiting agent, chloroquine (CQ), in combination with low concentrations of 5-fluorouracil (5-FU) increases the ability of tumor cells to induce DC maturation. DCs sensitized with the lysate of HCT-116 cells previously exposed to such a combination enhanced the DC maturation/activation ability. These matured DCs also increased the allogeneic responsiveness of both CD4+ and CD8+ T cells, which showed a greater proliferative response than those from DCs sensitized with control lysates. The T cells expanded in such cocultures were CD69+ and PD-1- and produced higher levels of IFN-γ and lower levels of IL-10, consistent with the preferential activation of Th1 cells. Cocultures of autologous DCs and lymphocytes improved the generation of cytotoxic T lymphocytes, as assessed by the expression of CD107a, perforin, and granzyme B. The drug combination increased the expression of genes related to the CEACAM family (BECN1, ATGs, MAPLC3B, ULK1, SQSTM1) and tumor suppressors (PCBP1). Furthermore, the decreased expression of genes related to metastasis and tumor progression (BNIP3, BNIP3L, FOSL2, HES1, LAMB3, LOXL2, NDRG1, P4HA1, PIK3R2) was noted. The combination of 5-FU and CQ increases the ability of tumor cells to drive DC maturation and enhances the ability of DCs to stimulate T cell responses., Competing Interests: Declaration of Competing Interest The authors declare no potential conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)