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.H epatocellular carcinoma (HCC), the most common primary liver cancer, is a dreaded complication of chronic liver disease that occurs in the setting of risk factors such as hepatitis B (HBV) and hepatitis C (HCV) viral infections, alcoholic liver disease, hemochromatosis, and nonalcoholic steatohepatitis (1). Most HCC appears in cirrhotic livers after years of chronic inflammation. The 5-year survival rate for patients with HCC, the increasing incidence of which is likely due to the spread of HCV (2), is only about 7%. Notably, men are about three to five times more likely to develop HCC than women (3). A similar or even more pronounced gender disparity is seen in rodent HCC models (4, 5). Furthermore, administration of estrogens to male mice inhibits development of chemically (DEN)-induced HCC (6). Nonetheless, the mechanisms that account for this gender disparity and the anticarcinogenic activity of estrogens are unknown.Inflammation is a major contributing factor to carcinogenesis (7). HCC represents a classic case of inflammation-linked cancer (8), and chemically or genetically induced HCC depends on inflammatory signaling (5, 9, 10). To understand the mechanisms underlying gender disparity in HCC, we used the chemical carcinogen diethylnitrosamine (DEN), which causes HCC in 100% of male mice but only in 10 to 30% of female littermates (5, 6). The pathogenesis of HCC in this mouse model differs from that in humans and thus may not be directly comparable to human HCC. Nevertheless, the mouse model of DENinduced HCC has a histology and genetic signature similar to that of human HCCs with poor prognosis (11) and recapitulates a dependence on inflammation and gender disparity seen in human HCC.Interleukin-6 (IL-6) is a multifunctional cytokine largely responsible for the hepatic re- (B) IL-6 mRNA levels in livers of male, female, or ovariectomized (OVX; ovariectomy was done 2 weeks before DEN administration) female mice 4 hours after DEN injection. E2 (50 mg/kg) in corn oil was injected intraperitoneally 2 hours before DEN was administered. (C) Male B6 mice (n = 3) were injected with ERa-specific ago...

SUMMARY Hepatocyte IκB kinase β (IKKβ) inhibits hepatocarcinogenesis by suppressing accumulation of reactive oxygen species (ROS) and liver damage, whereas JNK1 activation promotes ROS accumulation, liver damage and carcinogenesis. We examined whether hepatocyte p38α, found to inhibit liver carcinogenesis, acts similarly to IKKβ in control of ROS metabolism and cell death. Hepatocyte-specific p38α ablation enhanced ROS accumulation and liver damage, which were prevented upon administration of an antioxidant. In addition to elevated ROS accumulation, hepatocyte death, augmented by loss of either IKKβ or p38α, was associated with release of IL-1α. Inhibition of IL-1α action or ablation of its receptor inhibited carcinogen-induced compensatory proliferation and liver tumorigenesis. IL-1α release by necrotic hepatocytes is therefore an important mediator of liver tumorigenesis.

Attachment of Helicobacter pylori to gastric epithelial cells induces various cellular responses, including the tyrosine phosphorylation of an unknown 145-kD protein and interleukin 8 production. Here we show that this 145-kD protein is the cagA product of H. pylori, an immunodominant, cytotoxin-associated antigen. Epithelial cells infected with various H. pylori clinical isolates resulted in generation of tyrosine-phosphorylated proteins ranging from 130 to 145 kD in size that were also induced in vitro by mixing host cell lysate with bacterial lysate. When epithelial cells were infected with [35S]methionine-labeled H. pylori, a radioactive 145-kD protein was detected in the immunoprecipitates with antiphosphotyrosine antibody or anti-CagA (cytotoxin-associated gene A) antibody. Consistently, the 145-kD protein recognized by the anti-CagA and antiphosphotyrosine antibodies was induced in epithelial cells after infection of wild-type H. pylori but not the cagA::Km mutant. Furthermore, the amino acid sequence of the phosphorylated 145-kD protein induced by H. pylori infection was identical to the H. pylori CagA sequence. These results reveal that the tyrosine-phosphorylated 145-kD protein is H. pylori CagA protein, which may be delivered from attached bacteria into the host cytoplasm. The identification of the tyrosine-phosphorylated protein will thus provide further insights into understanding the precise roles of CagA protein in H. pylori pathogenesis.

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