Naugler, W. E. et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121-124

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Cancer Center, University of California, San Diego, CA 93093, USA.
Science (Impact Factor: 33.61). 08/2007; 317(5834):121-4. DOI: 10.1126/science.1140485
Source: PubMed


Hepatocellular carcinoma (HCC), the most common liver cancer, occurs mainly in men. Similar gender disparity is seen in mice
given a chemical carcinogen, diethylnitrosamine (DEN). DEN administration caused greater increases in serum interleukin-6
(IL-6) concentration in males than it did in females. Furthermore, ablation of IL-6 abolished the gender differences in hepatocarcinogenesis
in mice. DEN exposure promoted production of IL-6 in Kupffer cells (KCs) in a manner dependent on the Toll-like receptor adaptor
protein MyD88, ablation of which also protected male mice from DEN-induced hepatocarcinogenesis. Estrogen inhibited secretion
of IL-6 from KCs exposed to necrotic hepatocytes and reduced circulating concentrations of IL-6 in DEN-treated male mice.
We propose that estrogen-mediated inhibition of IL-6 production by KCs reduces liver cancer risk in females, and these findings
may be used to prevent HCC in males.

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    • "Hsu et al. also found anti-IL6 might suppress the MMP2 and MMP9 expressions in a colon cancer model[62]. Importantly, Karin et al. demonstrated estrogen and propyl pyrazole triol (PPT, ERα specific agonist) could suppress metastasis of hepatocellular carcinoma via inhibition of IL6 expression[63]. They also indicated that the gender difference in tumor susceptibility resulted from a downregulation of IL6 production by macrophages in response to estrogens. "
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    ABSTRACT: Background: Cancer associated fibroblasts (CAF) play important roles in tumor growth that involves inflammation and epithelial cell differentiation. Early studies suggested that estrogen receptor alpha (ERaα) was expressed in stromal cells in normal prostates and prostate cancer (PCa), but the detailed functions of stromal ERaα in the PCa remain to be further elucidated. Methods: Migration and invasion assays demonstrated the presence of high levels of ERaα in CAF cells (CAF.ERaα(+)) suppressed PCa invasion via influencing the infiltration of tumor associated macrophages. ERaα decreased CAF CCL5 secretion via suppressing the CCL5 promoter activity was examined by luciferase assay. ERaα decreased CCL5 and IL-6 expression in conditioned media that was collected from CAF cell only or CAF cell co-cultured with macrophages as measured by ELISA assay. Results: Both in vitro and in vivo studies demonstrated CAF.ERaα(+) led to a reduced macrophage migration toward PCa via inhibiting CAF cells secreted chemokine CCL5. This CAF.ERaα(+) suppressed macrophage infiltration affected the neighboring PCa cells invasion and the reduced invasiveness of PCa cells are at least partly due to reduced IL6 expression in the macrophages and CAF. Conclusion: Our data suggest that CAF ERaα could be applied as a prognostic marker to predict cancer progression, and targeting CCL5 and IL6 may be applied as an alternative therapeutic approach to reduce M2 type macrophages and PCa invasion in PCa patients with low or little ERaα expression in CAF cells.
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    • "In contrast, other experiments have reported a tumor-enhancing effect of ovariectomy on liver cancers (Vesselinovitch et al, 1980; Nakatani et al, 2001). In addition, rodent experiments have demonstrated the ability of estrogens to protect against diethylnitrosamine-induced liver cancer due to their ability to inhibit the production of interleukin-6 (IL-6), a multifunctional cytokine (Naugler et al, 2007). Whether a similar phenomenon occurs in human liver cancer is not clear. "
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    ABSTRACT: Background: Hepatocellular carcinoma (HCC) occurs less commonly among women than men in almost all regions of the world. The disparity in risk is particularly notable prior to menopause suggesting that hormonal exposures during reproductive life may be protective. Exogenous oestrogenic exposures such as oral contraceptives (OCs), however, have been reported to increase risk, suggesting that estrogens may be hepatocarcinogenic. To examine the effects of reproductive factors and exogenous hormones on risk, we conducted a prospective analysis among a large group of US women. Methods: In the Liver Cancer Pooling Project, a consortium of US-based cohort studies, data from 799,500 women in 11 cohorts were pooled and harmonised. Cox proportional hazards regression models were used to generate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of reproductive factors and exogenous hormones with HCC (n=248). Results: Bilateral oophorectomy was associated with a significantly increased risk of HCC (HR=2.67, 95% CI=1.22-5.85), which did not appear to be related to a shorter duration of exposure to endogenous hormones or to menopausal hormone therapy use. There was no association between OC use and HCC (HR=1.12, 95% CI=0.82-1.55). Nor were there associations with parity, age at first birth, age at natural menopause, or duration of fertility. Conclusions: The current study suggests that bilateral oophorectomy increases the risk of HCC but the explanation for the association is unclear. There was no association between OC use and HCC risk. Examination of endogenous hormone levels in relation to HCC may help to clarify the findings of the current study.
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    • "À/À mice are protected from a variety of pro-inflammatory diseases, such as RA (Alonzi et al., 1998), hepatocellular carcinoma (Naugler et al., 2007), and colitis (Gay et al., 2006), they paradoxically display mature-onset obesity, hepatosteatosis , liver inflammation, and insulin resistance (Matthews et al., 2010; Wallenius et al., 2002). Sgp130Fc transgenic mice show high serum levels of sgp130Fc (Figure S1A) resulting in impaired IL-6 trans-signaling but intact, membrane-bound IL-6R signaling and protection from inflammation (Rabe et al., 2008). "
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    ABSTRACT: Interleukin-6 (IL-6) plays a paradoxical role in inflammation and metabolism. The pro-inflammatory effects of IL-6 are mediated via IL-6 "trans-signaling," a process where the soluble form of the IL-6 receptor (sIL-6R) binds IL-6 and activates signaling in inflammatory cells that express the gp130 but not the IL-6 receptor. Here we show that trans-signaling recruits macrophages into adipose tissue (ATM). Moreover, blocking trans-signaling with soluble gp130Fc protein prevents high-fat diet (HFD)-induced ATM accumulation, but does not improve insulin action. Importantly, however, blockade of IL-6 trans-signaling, unlike complete ablation of IL-6 signaling, does not exacerbate obesity-induced weight gain, liver steatosis, or insulin resistance. Our data identify the sIL-6R as a critical chemotactic signal for ATM recruitment and suggest that selectively blocking IL-6 trans-signaling may be a more favorable treatment option for inflammatory diseases, compared with current treatments that completely block the action of IL-6 and negatively impact upon metabolic homeostasis. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Mar 2015 · Cell metabolism
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