Piperine inhibits IL-1β-induced IL-6 expression by suppressing p38 MAPK and STAT3 activation in gastric cancer cells

Abstract

Piperine, a kind of natural alkaloid found in peppers, has been reported to exhibit anti-oxidative and anti-tumor activities, both in vitro and in vivo. Interleukin-6 (IL-6) is an important cytokine that activates the signal transduction, promotes tumor cell metastasis, and induces malignancy, including in gastric cancer. However, the effects of piperine on IL-6 expression in gastric cancer cells have not yet been well defined. In this study, we investigated the effects of piperine on the IL-6 expression, and examined the underlying signaling pathways via RT-PCR, promoter studies and Western blotting in human gastric cancer TMK-1 cells. Our results showed that piperine inhibited interleukin-1β (IL-1β)-induced IL-6 expression in a dose-dependent manner. In addition, piperine also inhibited IL-6 promoter activity. Experiments with mitogen-activated protein kinase (MAPK) inhibitors and dominant negative mutant p38 MAPK indicated that p38 MAPK was essential for IL-6 expression in the TMK-1 cells. Additionally, signal transducer and activator of transcription 3 (STAT3) was also involved in the IL-1β-induced IL-6 expression in gastric cancer cells. Piperine inhibited IL-1β-induced p38 MAPK and STAT3 activation and, in turn, blocked the IL-1β-induced IL-6 expression. Furthermore, gastric cancer cells pretreated with IL-1β showed markedly enhanced invasiveness, which was partially abrogated by treatment with IL-6 siRNA, piperine, and inhibitors of p38 MAPK and STAT3. These results suggest that piperine may exert at least part of its anti-cancer effect by controlling IL-6 expression through the suppression of p38 MAPK and STAT3.

Intracellular Chloride Concentration Changes Modulate IL-1β Expression and Secretion in Human Bronchial Epithelial Cultured Cells

“…S3A), suggesting that IL-6 mRNA is stimulated by the IL-1b autocrine loop. These results are in agreement with reported results showing that IL-1b regulates IL-6 expression and secretion [Kandere-Grzybowska et al, 2006;Cahill and Rogers, 2008;Xia et al, 2015]. However, contrary to IL-1b, changes in Cl À from 5 to 75 mM showed no effects on the secretion of IL-6 ( Fig.…”

Nicotine stimulates IL‐6 expression by activating the AP‐1 and STAT‐3 pathways in human endothelial EA.hy926 cells

“…28 In the current study, we also established that the p38 MAPK signaling pathway, but not the ERK1/2 or JNK pathways, was essential for nicotine-induced IL-6 expression in endothelial EA.hy926 cells (Figure 2). Cells were incubated with 100 µg/mL nicotine for 0 to 120 minutes.…”

“…28,29 Therefore, we determined F I G U R E 4 The role of ROS in nicotine-induced IL-6 expression in human endothelial EA.hy926 cells. 28,29 Therefore, we determined F I G U R E 4 The role of ROS in nicotine-induced IL-6 expression in human endothelial EA.hy926 cells.…”

Anti‐Inflammatory Effects of Capsaicin and Piperine on Helicobacter pylori‐Induced Chronic Gastritis in Mongolian Gerbils

“…Il‐1β , Ifn‐γ , Il‐6, and iNos expression was attenuated only in the piperine‐treated gerbils. A recent report showed that piperine dose dependently inhibits IL‐1β‐induced IL‐6 expression in TMK‐1 gastric cancer cells . Several studies have also demonstrated that Ifn‐γ and Il‐6 play important roles in the progression of pyloric gastritis in H. pylori ‐infected gerbils .…”