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Gender Disparity in Liver Cancer Due to Sex Differences in MyD88-Dependent IL-6 Production
Willscott E. Naugler,1,2Toshiharu Sakurai,1Sunhwa Kim,1Shin Maeda,3KyoungHyun Kim,1Ahmed M. Elsharkawy,1,4Michael Karin1*
Hepatocellular carcinoma (HCC), the most common liver cancer,occurs mainly in men. Similar gender disparity is seen in micegiven a chemical carcinogen, diethylnitrosamine (DEN). DEN administrationcaused greater increases in serum interleukin-6 (IL-6) concentrationin males than it did in females. Furthermore, ablation of IL-6abolished the gender differences in hepatocarcinogenesis inmice. DEN exposure promoted production of IL-6 in Kupffer cells(KCs) in a manner dependent on the Toll-like receptor adaptorprotein MyD88, ablation of which also protected male mice fromDEN-induced hepatocarcinogenesis. Estrogen inhibited secretionof IL-6 from KCs exposed to necrotic hepatocytes and reducedcirculating concentrations of IL-6 in DEN-treated male mice.We propose that estrogen-mediated inhibition of IL-6 productionby KCs reduces liver cancer risk in females, and these findingsmay be used to prevent HCC in males.
1 Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Cancer Center, University of California, San Diego, CA 93093, USA. 2 Department of Medicine, Division of Gastroenterology, University of California, San Diego, CA 93093, USA. 3 Division of Gastroenterology, The Institute for Adult Diseases, Asahi Life Foundation, 1-6-1 Marunouchi, Chiyoda-ku, Tokyo 100-0005, Japan. 4 Liver Research Group, University of Newcastle, Newcastle Upon Tyne NE2 4HH, UK.
* To whom correspondence should be addressed: 9500 Gilman Road, Mail Code 0723 University of California, San Diego, San Diego, CA 92093–0636, USA. E-mail: karinoffice{at}ucsd.edu
Hepatocellular carcinoma (HCC), the most common primary livercancer, is a dreaded complication of chronic liver disease thatoccurs 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). MostHCC appears in cirrhotic livers after years of chronic inflammation.The 5-year survival rate for patients with HCC, the increasingincidence of which is likely due to the spread of HCV (2), isonly about 7%. Notably, men are about three to five times morelikely to develop HCC than women (3). A similar or even morepronounced gender disparity is seen in rodent HCC models (4,5). Furthermore, administration of estrogens to male mice inhibitsdevelopment of chemically (DEN)–induced HCC (6). Nonetheless,the mechanisms that account for this gender disparity and theanticarcinogenic 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 inflammatorysignaling (5, 9, 10). To understand the mechanisms underlyinggender disparity in HCC, we used the chemical carcinogen diethylnitrosamine(DEN), which causes HCC in 100% of male mice but only in 10to 30% of female littermates (5, 6). The pathogenesis of HCCin this mouse model differs from that in humans and thus maynot be directly comparable to human HCC. Nevertheless, the mousemodel of DEN-induced HCC has a histology and genetic signaturesimilar to that of human HCCs with poor prognosis (11) and recapitulatesa dependence on inflammation and gender disparity seen in humanHCC.
Interleukin-6 (IL-6) is a multifunctional cytokine largely responsiblefor the hepatic response to infections or systemic inflammation,oftentermedthe "acute phase response." Concentrations of IL-6in serum are increased in situations of chronic liver inflammationincluding alcoholic hepatitis, HBV and HCV infections, and steatohepatitis,conditions that may lead to development of HCC (12). IL-6 concentrationsare also increased in patients with HCC relative to normal subjects(13). Whether IL-6 is causal or contributory to HCC is unknown.However, IL-6 is thought to contribute to hepatocyte proliferation(14), and DEN administration to male mice results in IL-6 productionthat depends on IB kinase ß (IKKß) in myeloidcells, most likely the resident liver macrophages called Kupffercells (KCs). In addition to preventing IL-6 production, ablationof IKKß in myeloid cells prevents compensatory hepatocyteproliferation (5), a response triggered by hepatocyte death.
Compensatory proliferation appears to have a critical role inDEN-induced hepatocarcinogenesis (5, 10), and IL-6 is necessaryfor normal liver regeneration (14), so we examined gender effectson DEN-induced IL-6 production (15). Administration of DEN resultedin higher amounts of circulating IL-6 in males than in females(Fig. 1A). A similar gender bias was seen for accumulation ofIL-6 mRNA in liver (Fig. 1B). Administration of estradiol (E2)to male mice reduced IL-6 mRNA abundance, whereas ovariectomyaugmented accumulation of IL-6 mRNA in females. The latter waslargely prevented by E2 administration (Fig. 1B), as well asby the estrogen receptor (ER) agonist propylpyrazole-trisphenol(PPT) (Fig. 1C). No gender differences were seen in IL-6 expressionor hepatocyte proliferation after partial hepatectomy (fig.S1, A and B).
Fig. 1. Differential IL-6 production after chemically induced liver injury. (A) Concentration of IL-6 in serum of male and female WT mice after injection of DEN (100 mg per kg of body weight; n =3 mice per time point). (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 µg/kg)incornoilwas injected intraperitoneally 2 hours before DEN was administered. (C) Male B6 mice (n =3) were injected with ER-specific agonist propyl-pyrazole-trisphenol (PPT; 5 µg/kg in corn oil) 2 hours before DEN injection, and serum IL-6 was measured at the indicated times after DEN injection. Results in (A) to (C) are means ± SE. Asterisks indicate a significant (P < 0.05; Student's t test) difference relative to WT male mice.
[View Larger Version of this Image (13K GIF file)]
Pronounced gender-specific differences in IL-6 production werealso seen in mice treated with carbon tetrachloride (CCl4),a promoter of HCC development (fig. S2) (16). The cytotoxiceffects of DEN and CCl4 are dependent on their metabolic activationwithin the hepatocyte by cytochrome P450 2E1 (CYP 2E1) (17).Expression of CYP 2E1 did not differ between males and femalemice treated with DEN (fig. S3A). Once activated, DEN formsDNA adducts (18). DEN-induced DNA modification and damage shouldlead to activation of the p53-mediated genomic surveillanceresponse. Indeed, DEN administration led to rapid increase inexpression of the p53 target genes p21 and Mdm2, but the responsewas practically identical in males and females (fig. S3B).
To determine whether the gender bias in IL-6 production accountsfor the sex difference in HCC development, we examined DEN-inducedhepatocarcinogenesis in male and female IL-6 knockout (IL-6–/–)mice and wild-type (WT) controls. All male WT mice developedHCC, as did 13% of WT females (Fig. 2, A and B). A marked reductionin HCC incidence was seen in IL-6–/– males, whereasno difference was seen between WT and IL-6–/– females.In a cohort of mice monitored for survival, WT male mice exhibitedshorter mean survival times than IL-6–/– males orfemales of either genotype (Fig. 2C).
Fig. 2. Lower incidence of HCC tumors and longer survival of IL-6–/– mice. (A)Livers of 8-month-old DEN-treated mice. Multiple HCCs are seen only in WT male liver. (B) Incidence of HCC (> 0.5 mm) in WT male (n = 14), WT female (n = 13), IL-6–/– male (n = 14), and IL-6–/– female (n = 15) mice 8 months after DEN (25 mg/kg) injection. Asterisks indicate significant (P < 0.05; Student's t test) differences relative to WT male mice. (C) Survival curves of WT and IL-6–/– mice injected with DEN (25 mg/kg) at 15 days of age (P = 0.0006; log-rank test for significance).
[View Larger Version of this Image (41K GIF file)]
We examined the role of IL-6 in gender differences in short-termresponses elicited by DEN. Compared to WT animals, IL-6–/–males displayed significantly less hepatic injury after DENadministration as evidenced by reduced alanine aminotransferase(ALT) release (Fig. 3A), less apoptosis (Fig. 3B), and lessnecrosis (fig. S4A). Differences in compensatory proliferationmatched the degree of injury, such that IL-6–/–males exhibited fewer proliferating hepatocytes than WT counterpartsat 36 and 48 hours after DEN administration (Fig. 3C). Treatmentof male mice with an antagonistic antibody that blocks IL-6receptor signaling also provided protection from DEN-inducedliver injury (fig. S5).
Fig. 3. Influence of gender and IL-6 on hepatic injury and compensatory proliferation. (A)Male WT or IL-6–/– mice (n = 3) were given DEN (100 mg/kg), and ALT (alanine aminotransferase) in serum was measured. (B) Livers of male WT or IL-6–/– mice (n = 3) were assessed for apoptosis by TUNEL (terminal deoxynucleotidyl transferase– mediated dUTP nick-end labeling) staining after DEN injection. (C) Hepatocyte proliferation in livers of DEN-injected male WT or IL-6–/– mice (n = 3) was assessed by injecting mice with bromodeoxyrudine (BrdU) (1 mg per mouse) 2 hours before the liver was removed. BrdU-positive cells were identified by immunostaining. (D) Serum ALT was measured 48 hours after DEN injection (n = 3 per group). OVX: female mice ovariectomized 2 weeks before DEN administration. E2 (50 µg/kg) in corn oil was injected 2 hours before DEN. Similar studies assessing differences between male and female mice (n = 3) were done for apoptosis (E) and proliferation (F). (G) Six-week-old male B6 mice (n = 3) were given E2 or vehicle (corn oil) 2 hours before DEN injection. Recombinant IL-6 (10 µg) or sham buffer (phosphate-buffered saline) was given subcutaneously at the time of DEN administration. Serum ALT was measured 48 hours later. (H) Male ER–/– and ERß–/– mice and littermate heterozygote controls (n = 3) were injected with E2 (50 µg) in corn oil or vehicle 2 hours before DEN injection, and serum ALT was measured 50 hours later. (I)Malemice(n = 3 per point) were injected with PPT (5 mg/kg in corn oil) or vehicle 2 hours before DEN injection, and serum ALT was measured 50 hours later. All results for (A) to (I) are means ± SE, and asterisks indicate P < 0.05 (Student's t test). (J) Cells from livers of male, female, and IL-6–/– mice were lysed at the indicated times after DEN injection. STAT3 and JNK activation, and IB degradation, were assessed by separating with SDS–polyacrylamide gel electrophoresis and immunoblotting with antibodies to the indicated proteins. Phosphorylation (P) of STAT3 and JNK indicates activation. Phospho-STAT3 and STAT3 were from one gel, as were Phospho-JNK and JNK1/2, and IB and actin.
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Consistent with previous publications (19, 20), DEN-inducedliver injury was reduced in females or males given E2 2 hoursbefore DEN administration (Fig. 3D). Injury was increased inovariectomized females and reduced after E2 administration.Absence of IL-6 eliminated gender-related differences by reducingthe extent of injury in males (Fig. 3D). DEN-induced apoptosis(Fig. 3E), necrosis (fig. S4B), and compensatory proliferation(Fig. 3F) were greater in male than in female mice. Administrationof exogenous IL-6 augmented DEN-induced damage in both untreatedand E2-treated male mice (Fig. 3G). The reduction of injuryby E2 in IL-6– treated mice suggests that E2 may alsoattenuate downstream IL-6 signaling. Similar genderrelated differencesin liver injury were seen after administration of CCl4 (fig.S2).
Fig. 4. Requirement of MyD88 for IL-6 production, injury, and hepatocarcinogenesis after DEN treatment. (A)Accumulation of IL-6 mRNA was measured by real-time polymerase chain reaction in KCs from male WT, IKKß–/–, or MyD88–/– mice (n =3 experiments per time point) after incubation with LPS (10 ng/ml) or necrotic debris prepared by cycles of freezethawing of primary hepatocytes. Where indicated, cells were incubated with E2 (10 ng/ml) 30 min before stimulation. (B and C) Male WT and MyD88–/– mice were injected with DEN, and liver IL-6 mRNA (B) or serum ALT (C) was measured. (D and E) Number of HCCs(D) and sizes (E) in livers of WT and MyD88–/– male mice 8 months after DEN (25 mg/kg) administration. Results in (A) to (E) are means ± SE. Asterisks indicate a significant (P <0.05; Student's t test) difference relative to WT males.
[View Larger Version of this Image (13K GIF file)]
Using mice deficient in either ER or ERß, we foundthat ER is the receptor responsible for the protective effectof E2 (Fig. 3H), which was confirmed by decreased liver injuryin male mice pretreated with the ER-specific agonist PPT (Fig. 3I).
Another estrogen analog, tamoxifen, was found to act as a weakantagonist in this system and increase liver injury (fig. S6A).Absence of ER also increased DEN-induced injury in females (fig.S6A).
IL-6 activates the transcription factor STAT3 (21). The activatedform of STAT3 was absent in livers of IL-6–/– mice,and WT female mice exhibited less STAT3 activation than malesafter DEN administration (Fig. 3J). Female mice or IL-6–/–mice of both genders also exhibited reduced activation of themitogen-activated protein kinase JNK (c-Jun N-terminal kinase)at 12 hours after DEN administration, whereas little if anydifference was seen in DEN-induced IB degradation. Sustainedactivation of JNK is required for DEN-induced liver injury aswell as hepatocarcinogenesis (5, 10).
Estrogens inhibit IL-6 promoter activity by decreasing the activityof the transcription factors nuclear factor B(NF-B) and C/EBPß(22). KCs from male mice produced IL-6 when incubated with eitherbacterial lipopolysaccharide (LPS) or cellular debris releasedby necrotic hepatocytes (Fig. 4A). Both responses were stronglydependent on IKKß or the Toll-like receptor (TLR)adaptor protein MyD88 and were inhibited if the KCs were firstincubated with E2 (Fig. 4A). We speculated that necrotic debrisreleased by DEN-injured hepatocytes triggers cytokine productionand compensatory proliferation (5). The TLR adaptor MyD88, whichwas required for IL-6 induction by necrotic debris, was alsorequired for DEN-induced production of IL-6 in vivo (Fig. 4B)and for induction of liver injury (Fig. 4C). MyD88 was alsorequired for optimal CCl4-induced accumulation of IL-6 mRNA(fig. S7). MyD88 is also required for induction of liver injuryin response to hypoxia (23)and LPS (24). Furthermore, MyD88ablation suppressed DEN-induced hepatocarcinogenesis. MyD88–/–male mice developed fewer (Fig. 4D) and smaller (Fig. 4E) HCCtumors than WT male mice.
Administration of DEN also leads to modest accumulation of tumornecrosis factor– (TNF-) mRNA (5), another proinflammatorycytokine thought to be involved in liver regeneration (25).However, TNF- expression did not exhibit gender-dependent differences(fig. S8A), and ablation of TNF- or its type 1 receptor (TNFR1)had little if any effect on production of IL-6 in response toDEN (fig. S8B). Thus, IL-6 induction and liver injury are dependenton signaling via MyD88 but not through TNFR1. Accordingly, ablationof TNFR1 had no significant effect on DEN-induced hepatocarcinogenesis(fig. S8, C and D).
Our results explain why females are less prone to liver cancerthan males. This study and others (5, 10) show a strong correlationbetween the amount of liver damage during acute toxicity andinflammation and the extent of HCC development. We found thatboth liver injury and compensatory proliferation were stronglydependent on IL-6 and that the absence of this tumor-promotingcytokine resulted in almost complete inhibition of DEN-inducedhepatocarcinogenesis. IL-6 production by KCs was largely dependenton MyD88, an adaptor molecule that acts downstream of TLRs aswell as IL-1 receptor (26). Because DEN is not a direct macrophageor KC activator (27), hepatocyte necrosis may be an intermediatein the pathway through which DEN or CCl4 exposure results inIL-6 production. Various macromolecules released by necroticcells activate macrophages through TLRs, the receptors whichin turn activate MyD88 (28, 29). TRIF, another TLR adaptor protein(26), is not required for DEN- or CCl4-induced IL-6 productionand liver injury (27). MyD88 signaling, but not TNFR1 signaling,was required for optimal DEN-induced hepatocarcinogenesis inmale mice. DEN-induced hepatocarcinogenesis appears to dependon an inflammatory response, triggered by hepatocyte necrosis,that leads to production of IL-6. Estrogens, at concentrationspresent in females but not in males, suppress IL-6 productionand therefore inhibit chemically induced liver carcinogenesis.A similar mechanism could account for the gender bias in livercancer in humans. If so, estrogen-mimetic compounds capableof inhibiting excessive IL-6 production might be used to preventprogression of chronic liver disease to HCC in men.
27. In experiments performed in our laboratory, incubation of KCs or bone marrow–derived macrophages with DEN did not induce expression of IL-6 mRNA. DEN administration to TRIF–/– mice resulted in as much IL-6 induction as seen in WT mice.
30. We thank J. Feramisco for help with image capture and analysis and E. Karin for help with the surgical models. Supported by National Institute of Diabetes and Digestive and Kidney Diseases grant DK007202 (W.E.N.); Japan Society for the Promotion of Science (T.S.); Human Frontier Science Program (S.K.); and NIH grants ES004151 and ES006376, CA118165, and the Superfund Basic Research Program (M.K.). M.K. is an American Cancer Society Professor.
Received for publication 29 January 2007. Accepted for publication 4 June 2007.
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or ERß, we found that ER
B kinase ß (IKKß) in myeloid cells, most likely the resident liver macrophages called Kupffer cells (KCs). In addition to preventing IL-6 production, ablation of IKKß in myeloid cells prevents compensatory hepatocyte proliferation (
