Inhibition of IL-6 Signaling Pathway by Curcumin in Uterine Decidual Cells

Abstract

IL-6 is a multifunctional pro-inflammatory cytokine and has been implicated in many gestational disorders including preterm birth. Currently, there are no appropriate therapeutic interventions available to circumvent inflammatory-mediated gestational disorders. Therefore, the goal of this study was to identify a safe and effective pharmacological compound to counterbalance inflammatory responses in the uterus. Curcumin, a naturally-occuring polyphenolic compound, has been widely used in alternative medicine to treat inflammatory diseases. However, the anti-inflammatory effect of curcumin has not been explored in uterine decidual cells, a major source of IL-6. Therefore, we examined the effect of curcumin on IL-6 expression using two types of uterine decidual cells 1) HuF cells, primary human fibroblast cells obtained from the decidua parietalis; 2) UIII cells, a rodent non-transformed decidual cell line. Curcumin treatment completely abrogated the expression of IL-1β-induced IL-6 in these cells. Curcumin also strongly inhibited the expression of gp130, a critical molecule in IL-6 signaling, whereas expression of IL-6R and sIL-6R was not affected. Curcumin also inhibited phosphorylation and nuclear localization of STAT3, a well-known downstream mediator of IL-6 signaling. Furthermore, curcumin attenuated IL-1β-induced IL-6 promoter reporter activity suggesting transcriptional regulation. To further understand whether NF-ҡB is involved in this inhibition, we examined the effect of curcumin on the expression of p50 and p65 subunits of NF-ҡB in decidual cells. Expression of IL-1β-induced p50 mRNA was repressed by curcumin while p65 mRNA was not affected. However, curcumin treatment dramatically inhibited both p50 and p65 protein levels and prevented its nuclear localization. This effect is at least partly mediated through the deactivation of IKK, since IL-1β-induced IKKα/β phosphorylation is decreased upon curcumin treatment. Our results not only revealed molecular mechanisms underlying curcumin action in uterine decidual cells but also suggest that this compound may have therapeutic potential for the prevention of inflammation-mediated preterm birth and other gestational disorders.

Immunomodulatory effect of curcumin on lipopolysaccharide‐ and/or flagellin‐induced production of prostaglandin E2 and relative expression of proinflammatory cytokines in the primary bubaline endometrial stromal cells

“…Lipopolysaccharide significantly up-regulated the IL-1β transcripts, which is in accordance with the reports in the bovine epi- Similarly, topical application of curcumin along with substance P hastened the healing of cutaneous wounds by decreasing the mRNA levels for IL-1β and TNF-α (Kant et al, 2017). Curcumin completely abrogated the IL-1β-induced IL-6 expression in the human endometrial decidual cells, when used at a concentration of 5-30 µM without causing cell toxicity (Devi, DeVine, DeKuiper, Ferguson, & Fazleabas, 2015). Similarly, curcumin suppressed the TNF-α-induced F I G U R E 2 Effect of curcumin on lipopolysaccharide (LPS) and/or flagellininduced expression of (a) IL-1β (b) IL-6 (c) IL-8 and (d) TNF-α cytokines in the bubaline endometrial stromal cells.…”

“…Similarly, topical application of curcumin along with substance P hastened the healing of cutaneous wounds by decreasing the mRNA levels for IL‐1β and TNF‐α (Kant et al, ). Curcumin completely abrogated the IL‐1β‐induced IL‐6 expression in the human endometrial decidual cells, when used at a concentration of 5–30 µM without causing cell toxicity (Devi, DeVine, DeKuiper, Ferguson, & Fazleabas, ). Similarly, curcumin suppressed the TNF ‐ α‐induced production of IL‐1β, IL‐6 and IL‐8 expression of cell adhesion molecules in the human endometriotic stromal cells (Kim et al, ).…”

p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes

“…These drugs are primarily inhibitors of inflammatory pathway. Their targets included inhibition of NF-κB [55–58], enhancers of antiinflammatory peroxisome proliferator activated receptor (PPARs) [59], and antioxidant N-acetyl cysteine[60,61], cytokine suppressive anti-inflammatory drugs [62,63], agents to regulate Glycogen synthase kinase 3 (GSK3), an enzyme crucial for inflammation homeostasis [64], surfactant protein-A and PGJ2 to down regulate TLR mediated inflammation [65,66], targeted IL-6[67], and IL-1β signaling [68] to reduce inflammation, over antiinflammatory suppression using IL-10[69–71]. Although many of these (drugs) agents were successful in reducing inflammation or oxidative stress in vitro, some of them were shown to have toxic side effects in animal model trials or in clinical trials, and successful clinical trial outcomes are thus yet to be reported using any of these agents in reducing the risk of PTB.…”

The molecular mechanisms of curcumin’s inhibitory effects on cancer stem cells

“…81,82 In vivo and in vitro studies of CSC have shown that curcumin can inhibit the release and function of IL-6 in these cells. 83 Curcumin has also been found to be a potent inhibitor of IL-8 production, which reduces IL-8 receptor internalization, prevents acid-induced IL-8 production, and reduces IL-8 levels, in vitro. 83 Curcumin has also been found to be a potent inhibitor of IL-8 production, which reduces IL-8 receptor internalization, prevents acid-induced IL-8 production, and reduces IL-8 levels, in vitro.…”