Interleukin-6 Induced Proliferation Is Attenuated by Transforming Growth Factor-β-Induced Signaling in Human Hepatocellular Carcinoma Cells

Abstract

Hepatocellular carcinoma (HCC) is often associated with an inflammatory setting. A plethora of cytokines are secreted in this milieu, actively contributing to the progression of the disease; however, the extent of cytokine interaction and how it contributes to HCC development remains an enigma. In this regard, our analysis of available patient-derived data suggests that cytokines like interleukin-6 (IL-6) and transforming growth factor-beta (TGF-β) are enriched in HCC. We further analyzed the effect of these cytokines independently or in combination on HCC cells. Importantly, IL-6 was found to induce a STAT-3-dependent proliferation and mediate its pro-proliferative effects through activation and direct interaction with the p65 subunit of NFkB. Alternatively, TGF-β was found to induce a SMAD-dependent induction of epithelial to mesenchymal transition (EMT) coupled to growth arrest in these cells. Interestingly, the simultaneous addition of IL-6 and TGF-β failed to profoundly impact EMT markers but resulted in attenuation of IL-6-induced pro-proliferative effects. Analysis of the putative molecular mechanism revealed a decrease in IL-6 receptor (IL-6R) transcript levels, reduced expression of IL-6-induced STAT-3, and its nuclear localization upon addition of TGF-β along with IL-6. Consequently, a reduced p65 activation was also observed in combination treatment. Importantly, SMAD levels were unperturbed and the cells showed more TGF-β-like features under combination treatment. Finally, we observed that TGF-β resulted in enrichment of repressive chromatin mark (H3K27me3) coupled to growth arrest, while IL-6 induced an open chromatin signature (H3K4me3) associated with an enhanced expression of EZH2. Overall, for the first time, we show that TGF-β attenuates IL-6-induced effects by regulating the receptor level, downstream signaling, and the epigenome. Understanding the complex interactions between these cytokines can be imperative to a better understanding of the disease, and manipulation of cytokine balance can act as a prospective future therapeutic strategy.

METTL14 promotes IL‐6‐induced viability, glycolysis and inflammation in HaCaT cells via the m6A modification of TRIM27

“…To check the effects of IL‐6 in inducing cell viability, CCK‐8 assay was used for measuring cell viability after IL‐6 treatment. Agreeing with previous works, 18,27 cells treated with IL‐6 gradually manifested higher viability than those without IL‐6 treatment at 48 h ( p < 0.001; Figure 1B). Higher proliferative activities require quicker energy metabolism, that is, faster consumption of oxygen and energy, a signature behaviour of cancer cells 28 .…”

Toxicity evaluation of choline ionic liquid‐based nanocarriers of pharmaceutical agents for lung treatment

“…Such conclusions are promising, when the obtained results are compared also to the activation of pro‐inflammatory genes expression IL6 and IL8 (Figures 7–9). Used gene IL6, known also as markers of proliferation, survival and migration process 54 are much elevated in healthy bronchial cells, BEAS‐2B with even any expression in cancer A549 and H1299 cells (Figures 7–9). On the other side, the expression of pro‐inflammatory marker IL8, especially in lung diseases 55 is activated after LC derivative addition to the both cancer cell lines (Figures 8 and 9).…”

Study of some potential biomarkers in Egyptian hepatitis C virus patients in relation to liver disease progression and HCC

“…Binding of that cytokine to its receptor (IL-6R) produces a set of complicated signals which were proven to be tumor enhancement. Furthermore, it was shown that IL-6 exposure could lead to an increase in the expression of IL-6R, potentially leading in a feedback loop that amplifies the IL-6-induced impact [ 39 ].…”