Elevated interleukin-6 during ethanol consumption acts as a potential endogenous protective cytokine against ethanol-induced apoptosis in the liver: involvement of induction of Bcl-2 and Bcl-xL proteins
Abstract
Elevation of serum interleukin-6 (IL-6) levels is always associated with alcoholic liver disease (ALD), but the significance of such elevation is not clear. Here we show that chronic ethanol consumption induces significant apoptosis in the liver of IL-6 (-/-) mice but not IL-6 (+/+) mice. IL-6 (-/-) hepatocytes are more susceptible to ethanol- and tumor necrosis factor alpha- (TNFalpha-) induced apoptotic killing, which can be corrected by IL-6. Expression of both anti-apoptotic (such as Bcl-2 and Bcl-x(L)) and proapoptotic (such as Bax) proteins is markedly elevated in the liver of human ALD and chronically ethanol-fed IL-6 (+/+) mice. On the contrary, induction of Bcl-2 and Bcl-x(L) is not observed in the liver of chronically ethanol-fed IL-6 (-/-) mice, whereas expression of Bax protein remains elevated. Injection of IL-6 markedly induces expression of Bcl-2 and Bcl-x(L) but not Bax in the liver. Finally, high concentrations of ethanol inhibit IL-6-activated anti-apoptotic signal, but increasing the concentrations of IL-6 is able to overcome such inhibitory effect. These findings suggest that elevated serum IL-6 levels in ALD may overcome the inhibitory effect of ethanol on IL-6-mediated anti-apoptotic signals and prevent alcohol-induced hepatic apoptosis by induction of Bcl-2 and Bcl-x(L).
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IL-6 has a protective role during liver injury.
“Increasing evidence demonstrates that IL-6 has a protective role during liver injury.”
From The IL-6–gp130–STAT3 pathway in hepatocytes triggers liver protection in T cell–mediated liver injury (2005) · cites this paper as [4]
Cites
Liver Failure and Defective Hepatocyte Regeneration in Interleukin-6-Deficient Mice
Cressman, D. E., Greenbaum, L. E., DeAngelis, R. A., Ciliberto, G., Furth, E. E., Poli, V., & Taub, R. (1996) · Science · doi:10.1126/science.274.5291.1379 · Cited by 1,536 · see citing works
Increased toxin-induced liver injury and fibrosis in interleukin-6-deficient mice
Kovalovich, K., DeAngelis, R. A., Li, W., Furth, E. E., Ciliberto, G., & Taub, R. (2000) · Hepatology · doi:10.1002/hep.510310123 · Cited by 298 · see citing works
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Radaeva, S., Sun, R., Pan, H., Hong, F., & Gao, B. (2004) · Hepatology · doi:10.1002/hep.20184 · Cited by 638 · see citing works
Self-citationOpposing roles of STAT1 and STAT3 in T cell–mediated hepatitis: regulation by SOCS
Hong, F., Jaruga, B., Kim, W. H., Radaeva, S., El-Assal, O. N., Tian, Z., Nguyen, V.-A., & Gao, B. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15841 · Cited by 291 · see citing works
“Additionally, induction of the antiapoptotic Bcl-XL protein expression in hepatocytes may be another mechanism contributing to IL-6/STAT3-mediated protection against Con A– induced liver injury because Bcl-XL, which is elevated and positively regulated by IL-6/STAT3 in Con A– induced hepatitis (Figure 2d and Figure 5a…”
Self-citationAdvanced body composition assessment: from body mass index to body composition profiling
Irace, C., de Rosa, S., Tripolino, C., Ambrosio, G., Covello, C., Abramo, E., Carallo, C., Mongiardo, A., Spaccarotella, C., Torella, D., et al. (2018) · Journal of Investigative Medicine · doi:10.1136/jim-2017-000618 · Cited by 313 · see citing works
Molecular Mechanisms of Alcoholic Fatty Liver
Purohit, V., Gao, B., & Song, B. (2009) · Alcoholism: Clinical and Experimental Research · doi:10.1111/j.1530-0277.2008.00827.x · Cited by 312 · see citing works
“…IL-6-deficient mice are more susceptible to alcohol-induced steatosis and liver injury, while treatment with IL-6 ameliorates alcohol-induced fatty liver and prevents mortality associated with alcoholic fatty liver transplants (El-Assal et al., 2004; Hong et al., 2002, 2004; Sun et al., 2003).”
Self-citationCellular and Mitochondrial Effects of Alcohol Consumption
Manzo‐Ávalos, S., & Saavedra‐Molina, A. (2010) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph7124281 · Cited by 297 · see citing works
“Treatment of steatosis with IL-6 induces expression of anti-apoptotic Bcl-xL protein in primary mouse hepatocytes [161],”
BackgroundInflammation in Alcoholic Liver Disease
Wang, H. J., Gao, B., Zakhari, S., & Nagy, L. E. (2012) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-072610-145138 · Cited by 298 · see citing works
Self-citationAverting inflammation by targeting the cytokine environment
Köpf, M., Bachmann, M. F., & Marsland, B. J. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd2805 · Cited by 256 · see citing works
“and protects against a multitude of liver-damaging influences including alcoho”
BackgroundSozio, M., & Crabb, D. (2008) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.00011.2008 · Cited by 256 · see citing works
The Effect of Inflammatory Cytokines in Alcoholic Liver Disease
Kawaratani, H., Tsujimoto, T., Douhara, A., Takaya, H., Moriya, K., Namisaki, T., Noguchi, R., Yoshiji, H., Fujimoto, M., & Fukui, H. (2013) · Mediators of Inflammation · doi:10.1155/2013/495156 · Cited by 258 · see citing works
“IL-6 may protect against hepatocyte apoptosis and participate in mitochondrial DNA repair after alcoholic liver injury [30, 31].”
BackgroundHong, F., Radaeva, S., Pan, H., Tian, Z., Veech, R. L., & Gao, B. (2004) · Hepatology · doi:10.1002/hep.20400 · Cited by 202 · see citing works
Self-citationKlein, C., Wüstefeld, T., Assmus, U., Roskams, T., Rose-John, S., Müller, M., Manns, M. P., Ernst, M., & Trautwein, C. (2005) · Journal of Clinical Investigation · doi:10.1172/jci200523640 · Cited by 200 · see citing works
Hepatoprotective and anti-inflammatory cytokines in alcoholic liver disease
Gao, B. (2012) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2011.07003.x · Cited by 193 · see citing works
Self-citationHoriguchi, N., Wang, L., Mukhopadhyay, P., Park, O., Jeong, W.-I., Lafdil, F., Osei-Hyiaman, D., Moh, A., Fu, X.-Y., Pacher, P., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.01.016 · Cited by 185 · see citing works
Self-citationMolecular mechanisms of alcoholic liver disease: Innate immunity and cytokines
Miller, A. M., Horiguchi, N., Jeong, W., Radaeva, S., & Gao, B. (2011) · Alcoholism: Clinical and Experimental Research · doi:10.1111/j.1530-0277.2010.01399.x · Cited by 176 · see citing works
“, 2003); Finally, in vitro treatment with IL-6 prevents ethanol plus TNF-a-induced mouse hepatocyte apoptosis (Hong et al., 2002).”
BackgroundInfluentialSelf-citationParadoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair
Jin, X., Zimmers, T. A., Perez, E. A., Pierce, R. H., Zhang, Z., & Koniaris, L. G. (2006) · Hepatology · doi:10.1002/hep.21087 · Cited by 173 · see citing works
Exosomes derived from human menstrual blood-derived stem cells alleviate fulminant hepatic failure
Chen, L., Xiang, B.-Y., Wang, X.-J., & Xiang, C. (2017) · Stem cell research & therapeutics · doi:10.1186/s13287-016-0453-6 · Cited by 171 · see citing works
“Generally, IL-6 has been known to act as a pro-survival factor, which can stimulate hepatocyte proliferation [39, 40].”
Jaruga, B., Hong, F., Sun, R., Radaeva, S., & Gao, B. (2003) · Journal of Immunology · doi:10.4049/jimmunol.171.6.3233 · Cited by 164 · see citing works
“Anti-STAT1, anti-phospho-STAT1 (Tyr701), anti-phospho-STAT3 (Tyr705), anti-STAT3, anti-phospho-STAT6 (Tyr641), anti-STAT6, and anti-phosphoI B Abs were obtained from Cell Signaling Technology (Beverly, MA).”
BackgroundInfluentialSelf-citationMicroencapsulated human mesenchymal stem cells decrease liver fibrosis in mice
Meier, R. P. H., Mahou, R., Morel, P., Meyer, J., Montanari, E., Muller, Y. D., Christofilopoulos, P., Wandrey, C., Gonelle-Gispert, C., & Bühler, L. H. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2014.10.030 · Cited by 153 · see citing works
n-3 Polyunsaturated fatty acids for the management of alcoholic liver disease: A critical review
Wang, M., Ma, L.-J., Yang, Y., Xiao, Z., & Wan, J.-B. (2019) · Critical reviews in food science and nutrition · doi:10.1080/10408398.2018.1544542 · Cited by 149 · see citing works
“IL-6-deficient mice exhibited more susceptibility to alcoholic liver injury (El-Assal et al., 2004; Hong et al., 2002; Zhang et al., 2010).”
BackgroundGastroprotective effect of crocin in ethanol-induced gastric injury in rats.
el-Maraghy, S. E., Rizk, S., & Shahin, N. N. (2015) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2015.01.015 · Cited by 143 · see citing works
Das, S., Santra, A., Lahiri, S., & Mazumder, D. G. G. (2005) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2004.08.010 · Cited by 139 · see citing works
Sun, Z., Klein, A. S., Radaeva, S., Hong, F., El-Assal, O. N., Pan, H.-N., Jaruga, B., Bátkai, S., Hoshino, S., Tian, Z., et al. (2003) · Gastroenterology · doi:10.1016/s0016-5085(03)00696-6 · Cited by 126 · see citing works
Self-citationMasubuchi, Y., Bourdi, M., Reilly, T. P., Graf, M. L. M., George, J. W., & Pohl, L. R. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)00572-2 · Cited by 145 · see citing works
Mesenchymal stem cells and Interleukin-6 attenuate liver fibrosis in mice
Nasir, G. A., Mohsin, S., Khan, M., Shams, S., Ali, G., Khan, S. N., & Riazuddin, S. A. (2013) · Journal of Translational Medicine · doi:10.1186/1479-5876-11-78 · Cited by 125 · see citing works
“Recent studies show that IL-6−/− mice demonstrate hepatocyte apoptosis after treatment with ethanol emphasizing the role of IL-6 in liver protection against drug induced hepatoxicity [35].”
BackgroundSynthesis of IL-6 by Hepatocytes Is a Normal Response to Common Hepatic Stimuli
Norris, C. A., He, M., Kang, L.-I., Ding, M. Q., Radder, J. E., Haynes, M. M., Yang, Y., Paranjpe, S., Bowen, W. C., Orr, A., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0096053 · Cited by 132 · see citing works
“Although IL-6 has been detected in the media of primary hepatocytes in culture before [26], it was generally interpreted as likely to be originating from contaminating macrophages.”
BackgroundPal-Bhadra, M., Bhadra, U., Jackson, D. E., Mamatha, L., Park, P.-H., & Shukla, S. D. (2007) · Life Science · doi:10.1016/j.lfs.2007.07.030 · Cited by 130 · see citing works
“…metabolism (Morimoto et al., 1993; Ronis et al., 1993; Deaciuc et al., 2004a,b) cell signaling (Mochly-Rosen et al., 1988; Gordon et al., 1986; Hong et al., 2002a,b) and apoptosis (Yacoub et al., 1995; Deaciuc et al., 1999; Deaciuc et al., 2002a,b; Koteish et al., 2002) are highly sensitive…”
BackgroundChen, L., Zhang, C., Chen, L., Wang, X., Xiang, B., Wu, X., Guo, Y., Mou, X., Yuan, L., Chen, B., et al. (2016) · Stem Cells Translational Medicine · doi:10.5966/sctm.2015-0265 · Cited by 142 · see citing works
Mechanism investigation of dioscin against CCl4-induced acute liver damage in mice.
Lu, B.-N., Xu, Y.-S., Xu, L.-N., Cong, X.-N., Yin, L., Li, H., & Peng, J.-Y. (2012) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2012.03.010 · Cited by 107
Sun, R., Tian, Z., Kulkarni, S., & Gao, B. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.9.5648 · Cited by 86 · see citing works
“I nterleukin-6 is a pleiotropic cytokine that has been shown to promote liver regeneration (1) and protect against liver injury induced by Con A (2, 3), alcohol (4), Fas (5), carbon tetrachloride (CCl4) (6), ischemia/reperfusion (7), acetaminophen (8), hemorrhagic shock (9), partial liver transplantation (10), and fat…”
BackgroundSelf-citationBaj, J., Flieger, W., Teresiński, G., Buszewicz, G., Sitarz, R., Forma, A., Karakuła, K., & Maciejewski, R. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9061901 · Cited by 93 · see citing works
“These processes lead to cell damage and stimulation of inflammatory reactions releasing a large number of cytokines, among others such as TNF-alpha and IL-6 [21,22].”
BackgroundIL-6 Deficiency Attenuates Murine Diet-Induced Non-Alcoholic Steatohepatitis
Mas, E., Danjoux, M., Garcia, V., Carpentier, S., Ségui, B., & Levade, T. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007929 · Cited by 89 · see citing works
Cell-to-cell and organ-to-organ crosstalk in the pathogenesis of alcohol-associated liver disease
Gao, H., Jiang, Y., Zeng, G., Huda, N., Thoudam, T., Yang, Z.-H., Liangpunsakul, S., & Ma, J. (2024) · eGastroenterology · doi:10.1136/egastro-2024-100104 · Cited by 85 · see citing works
Diabetes Mellitus and Risk of Hepatocellular Carcinoma
Li, X., Wang, X., & Gao, P. (2017) · BioMed Research International · doi:10.1155/2017/5202684 · Cited by 86 · see citing works
Bourdi, M., Eiras, D., Holt, M. P., Webster, M. R., Reilly, T., Welch, K., & Pohl, L. (2007) · Chemical Research in Toxicology · doi:10.1021/tx060228l · Cited by 80 · see citing works
Pathogenesis of alcoholic liver disease: the role of nuclear receptors
Gyamfi, M. A., & Wan, Y. Y. (2010) · Experimental Biology and Medicine · doi:10.1258/ebm.2009.009249 · Cited by 74 · see citing works
Yue, S., Xue, N., Li, H.-L., Huang, B.-S., Chen, Z., & Wang, X. (2020) · Inflammation · doi:10.1007/s10753-020-01238-5 · Cited by 78 · see citing works
“Elevation of pro-inflammatory cytokines like TNFα and IL-6 is strongly associated with liver injury [32].”
BackgroundQu, L.-L., Zhu, Y., Liu, Y.-N., Yang, H.-X., Zhu, C.-H., Ma, P., Deng, J., & Fan, D.-D. (2019) · Food and Chemical Toxicology · doi:10.1016/j.fct.2019.02.032 · Cited by 74 · see citing works
Role of monocytes and macrophages in experimental and human acute liver failure.
Possamai, L., Antoniades, C., Anstee, Q., Quaglia, A., Vergani, D., Thursz, M., & Wendon, J. (2010) · World Journal of Gastroenterology · doi:10.3748/wjg.v16.i15.1811 · Cited by 74 · see citing works
Zhang, X., Tachibana, S., Wang, H., Hisada, M., Williams, G. M., Gao, B., & Sun, Z. (2010) · Hepatology · doi:10.1002/hep.23909 · Cited by 73 · see citing works
“IL-6 reduces fatty changes caused by alcohol feeding in mice, and that the mechanism is related to improved mitochondrial function.(23,24) We have reported that in vitro IL-6 treatment markedly reduced mortality associated with fatty liver transplants from alcohol-fed rats.”
BackgroundSelf-citationThe role of human cytochrome P450 2E1 in liver inflammation and fibrosis
Xu, J., Ma, H., Liang, S., Sun, M., Karin, G., Koyama, Y., Hu, R., Quehenberger, O., Davidson, N. O., Dennis, E. A., et al. (2017) · Hepatology Communications · doi:10.1002/hep4.1115 · Cited by 77 · see citing works
Williams, M. J. A., Sutherland, W. H. F., Whelan, A. P., McCormick, M. P., & de Jong, S. A. (2004) · Metabolism · doi:10.1016/j.metabol.2003.10.012 · Cited by 70 · see citing works
Cytokines in alcoholic liver disease
An, L., Wang, X., & Cederbaum, A. (2012) · Archives of Toxicology · doi:10.1007/s00204-012-0814-6 · Cited by 69 · see citing works
Crabb, D. W., & Liangpunsakul, S. (2006) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2006.04582.x · Cited by 69 · see citing works
Han, J. H., Ju, J., Lee, Y.-S., Park, J. H., Yeo, I., Park, M., Roh, Y., Han, S., & Hong, J. (2018) · Scientific Reports · doi:10.1038/s41598-018-32497-w · Cited by 68 · see citing works
Ethanol consumption modifies dendritic cell antigen presentation in mice.
Heinz, R. E., & Waltenbaugh, C. (2007) · Alcoholism: Clinical and Experimental Research · doi:10.1111/j.1530-0277.2007.00479.x · Cited by 68 · see citing works
Alcohol and mitochondria in cardiac apoptosis: mechanisms and visualization.
Hajnóczky, G., Buzas, C., Pacher, P., Hoek, J., & Rubin, E. (2005) · Alcoholism: Clinical and Experimental Research · doi:10.1097/01.alc.0000163493.45344.7a · Cited by 68 · see citing works
A review on molecular mechanism of alcoholic liver disease.
Namachivayam, A., & Gopalakrishnan, A. V. (2021) · Life Science · doi:10.1016/j.lfs.2021.119328 · Cited by 67 · see citing works
Mesenchymal stromal cells and liver fibrosis: a complicated relationship
Haldar, D., Henderson, N. C., Hirschfield, G. M., & Newsome, P. N. (2016) · The FASEB Journal · doi:10.1096/fj.201600433r · Cited by 81 · see citing works
“IL-6 has wellrecognized cytoprotective functions (110).”
JAK-STAT signaling in hepatic fibrosis
Mair, M. (2011) · Frontiers in bioscience · doi:10.2741/3886 · Cited by 63 · see citing works
“IL-6-deficient mice are more susceptible to liver injury induced by ethanol (60), Con A (46, 61) acetaminophen (62, 63) and bile acids (64), suggesting that IL-6 has protective functions (65, 66).”
BackgroundGyamfi, M. A., He, L., French, S. W., Damjanov, I., & Wan, Y. Y. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.132258 · Cited by 60 · see citing works
Targeting inflammation for the treatment of alcoholic liver disease,
Xu, M.-J., Zhou, Z., Parker, R., & Gao, B. (2017) · Pharmacology and Therapeutics · doi:10.1016/j.pharmthera.2017.06.007 · Cited by 66 · see citing works
Self-citationWang, L., Qiu, J.-P., Yu, L., Hu, X.-L., Zhao, P., & Jiang, Y.-F. (2014) · Journal of Translational Medicine · doi:10.1186/s12967-014-0251-9 · Cited by 66
“IL-10 can inhibit inflammation and be a protector of liver injury by inducing Bcl-2 and BclxL expression [49,50], and there is no direct evidence that IL-10 causes liver injury.”
BackgroundHong, E., Levasseur, M.-P., Dufour, C. R., Perry, M.-C., & Giguère, V. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1315319110 · Cited by 70 · see citing works
“In addition, IL-6 has been found to prevent apoptosis by inducing Bcl-2 and Bcl2l1 (Bcl-xl) levels (38, 39).”
BackgroundOgnjanovic, S., Yuan, J.-M., Chaptman, A. K., Fan, Y.-H., & Yu, M.-M. C. (2009) · Carcinogenesis · doi:10.1093/carcin/bgn286 · Cited by 66 · see citing works
Pastorino, J., Shulga, N., & Hoek, J. (2003) · American Journal of Physiology - Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00442.2002 · Cited by 65 · see citing works
Anti-inflammatory and anti-apoptotic roles of endothelial cell STAT3 in alcoholic liver injury
Miller, A. M., Wang, H., Park, O., Horiguchi, N., Lafdil, F., Mukhopadhyay, P., Moh, A., Fu, X.-Y., Kunos, G., Pacher, P., et al. (2010) · Alcoholism: Clinical and Experimental Research · doi:10.1111/j.1530-0277.2009.01141.x · Cited by 64 · see citing works
“First, IL6-deficient mice are more susceptible to alcohol-induced hepatic steatosis and apoptosis (El-Assal et al., 2004; Hong et al., 2002).”
Self-citationIntragraft gene expression profiles by cDNA microarray in small‐for‐size liver grafts
Man, K., Lo, C., Lee, T., Li, X.-L., Ng, I., & Fan, S. (2003) · Liver transplantation · doi:10.1053/jlts.2003.50066 · Cited by 64
Hu, S.-L., Shen, G., Zhao, W., Wang, F., Jiang, X.-D., & Huang, D.-B. (2010) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2009.12.034 · Cited by 62
McConnell, M., Kondo, R., Kawaguchi, N., & Iwakiri, Y. (2021) · Hepatology Communications · doi:10.1002/hep4.1843 · Cited by 60 · see citing works
Therapeutic strategies for alcoholic liver disease: Focusing on inflammation and fibrosis (Review)
Kawaratani, H., Moriya, K., Namisaki, T., Uejima, M., Kitade, M., Takeda, K., Okura, Y., Kaji, K., Takaya, H., Nishimura, N., et al. (2017) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2017.3015 · Cited by 65 · see citing works
“In contrast, IL-6-knockout chronically alcohol-fed mice were found to have increased liver fat accumulation, lipid peroxidation, mitochondrial DNA damage, and sensitization of hepatocytes to TNF-α -induced apoptosis (28,33).”
Cheng, L., Wang, J., Li, X., Xing, Q. R., Du, P., Su, L., & Wang, S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017631 · Cited by 55 · see citing works
Hepatocyte toll-like receptor 4 deficiency protects against alcohol-induced fatty liver disease
Jia, L., Chang, X., Qian, S., Liu, C., Lord, C. C., Ahmed, N., Lee, C. E., Lee, S., Gautron, L., Mitchell, M. C., et al. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.05.015 · Cited by 54 · see citing works
Large-scale gene profiling of the liver in a mouse model of chronic, intragastric ethanol infusion.
Deaciuc, I., Doherty, D., Burikhanov, R., Lee, E. Y., Stromberg, A., Peng, X., & de Villiers, W. D. (2004) · Journal of Hepatology · doi:10.1016/j.jhep.2003.10.021 · Cited by 53 · see citing works
Execution of Superoxide-Induced Cell Death by the Proapoptotic Bcl-2-Related Proteins Bid and Bak
Madesh, M., Zong, W.-X., Hawkins, B., Ramasamy, S., Venkatachalam, T., Mukhopadhyay, P., Doonan, P. J., Irrinki, K. M., Rajesh, M., Pacher, P., et al. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01845-08 · Cited by 51 · see citing works
Horiguchi, N., Ishac, E., & Gao, B. (2007) · Alcohol · doi:10.1016/j.alcohol.2007.04.008 · Cited by 51 · see citing works
“IL-6 activation of STAT3 in the liver is also involved in induction of acute phase proteins and in protection of the liver against a wide variety of insults including ethanol (Gao, 2005;Hong et al., 2002;Hong et al., 2004;Sun et al., 2003).”
BackgroundSelf-citationRole of the proteasome in ethanol-induced liver pathology.
Donohue, T., Cederbaum, A., French, S., Barve, S., Gao, B., & Osna, N. (2007) · Alcoholism: Clinical and Experimental Research · doi:10.1111/j.1530-0277.2007.00454.x · Cited by 50 · see citing works
Self-citationThe pathogenesis of ethanol versus methionine and choline deficient diet-induced liver injury
Gyamfi, M. A., Damjanov, I., French, S. W., & Wan, Y. Y. (2007) · Biochemical Pharmacology · doi:10.1016/j.bcp.2007.09.030 · Cited by 53 · see citing works
Bedirli, A., Kerem, M., Paşaoğlu, H., Erdem, Ö., Ofluoğlu, E., & Şakrak, Ö. (2005) · Journal of Surgical Research · doi:10.1016/j.jss.2004.11.028 · Cited by 43 · see citing works
“In addition to this signaling effect on hepatocyte proliferation, IL-6 also protects the liver against various forms of liver injury, such as ischemia and reperfusion [22], toxins [24], and cell death mediated by Fas activation [25].”
BackgroundImmunology in alcoholic liver disease
Duddempudi, A. T. (2012) · Clinics in Liver Disease · doi:10.1016/j.cld.2012.08.003 · Cited by 47 · see citing works
Niu, X., Liu, F., Li, W.-F., Zhi, W., Yao, Q., Zhao, J., Yang, G.-X.-X., Wang, X.-M., Qin, L., & He, Z.-H. (2017) · Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · doi:10.1016/j.biopha.2017.09.029 · Cited by 47 · see citing works
Rollwagen, F., Madhavan, S., Singh, A., Li, Y.-Y., Wolcott, K., & Maheshwari, R. (2006) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2006.07.016 · Cited by 47 · see citing works
Beraza, N., Marqués, J. M., Martínez-Ansó, E., Íñiguez, M., Prieto, J., & Bustos, M. (2005) · Hepatology · doi:10.1002/hep.20590 · Cited by 47 · see citing works
Ethanol promotes T cell apoptosis through the mitochondrial pathway
Kapasi, A. A., Patel, G., Goenka, A., Nàhàr, N., Modi, N., Bhaskaran, M., Reddy, K., Franki, N., Patel, J., & Singhal, P. C. (2003) · Immunology · doi:10.1046/j.1365-2567.2003.01584.x · Cited by 47 · see citing works
Interleukin-6 deficiency accelerates cisplatin-induced acute renal failure but not systemic injury.
Mitazaki, S., Kato, N., Suto, M., Hiraiwa, K., & Abe, S. (2009) · Toxicology · doi:10.1016/j.tox.2009.10.005 · Cited by 45
Tachibana, S., Zhang, X., Ito, K., Ota, Y., Cameron, A. M., Williams, G. M., & Sun, Z. (2014) · Cell & Bioscience · doi:10.1186/2045-3701-4-6 · Cited by 43 · see citing works
Inhibitory Effect of Gardenoside on Free Fatty Acid-Induced Steatosis in HepG2 Hepatocytes
Liang, H.-Q., Zhang, L.-M., Wang, H.-G., Tang, J.-M., Yang, J.-E., Wu, C.-C., & Chen, S.-D. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms161126058 · Cited by 43 · see citing works
“Similarly, a principal hypothesis posted that in situ ations where an injury is inflicted directly upon the liver, it is the resident immune cells, such as the Kupffer cells (hepatic macrophages), that primarily produce the IL-6 used for stimulating acute phase protein production [29–31].”
BackgroundPhysiological potential of cytokines and liver damages
Mannaa, F., & Abdel-Wahhab, K. G. (2016) · Hepatoma Research · doi:10.20517/2394-5079.2015.58 · Cited by 42 · see citing works
“IL-6 may protect against hepatocyte apoptosis and participates in mitochondrial DNA repair after alcoholic liver injury.[26] IL-6 may promote human Figure 3: Interleukin 1 (IL-1) antagonism: IL-1 activity at the receptor may be”
BackgroundYuan, F., Chen, X., Liu, J., Feng, W., Wu, X., & Chen, S. (2016) · Archives of Toxicology · doi:10.1007/s00204-016-1746-3 · Cited by 45 · see citing works
“1 3 Multiple signaling pathways have been demonstrated to be involved in ethanol-induced apoptosis, including Bcl-2 family (Hong et al. 2002), Fas/Fas-L and p53 pathways (Jana et al.”
Han, C. L., Bowen, W. C., Michalopoulos, G. K., & Wu, T. (2008) · Journal of Cellular Physiology · doi:10.1002/jcp.21420 · Cited by 49 · see citing works
“Mice with disruption of IL-6 show impaired liver regeneration (Cressman et al., 1996; Sakamoto et al., 1999) and are susceptible to liver injury induced by carbon tetrachloride (Kovalovich et al., 2000), Fas (Kovalovich et al., 2001), and ethanol (Hong et al., 2002).”
BackgroundGao, B. (2004) · Alcohol · doi:10.1016/j.alcohol.2004.07.006 · Cited by 31 · see citing works
Self-citationHu, C.-Q., Bo, Q.-L., Chu, L.-L., Hu, Y.-D., Fu, L., Wang, G.-X., Lu, Y., Liu, X.-J., Wang, H., & Xu, D.-X. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/5715893 · Cited by 33 · see citing works
“It is established that the release of inflammatory cytokines leads to hepatocyte apoptosis, as well as ROS accumulation and oxidative stress [51, 52].”
BackgroundCai, X.-X., Bao, L., Wang, N., Ren, J., Chen, Q., Xu, M.-H., Li, D., Mao, R.-X., & Li, Y. (2016) · Food & Function · doi:10.1039/c5fo01580d · Cited by 33 · see citing works
Riordan, S. M., Skinner, N. A., McIver, C. J., Liu, Q., Bengmark, S., Bihari, D. J., & Visvanathan, K. (2007) · Microbial Ecology in Health and Disease · doi:10.1080/08910600601178709 · Cited by 29 · see citing works
“In particular, IL-6 has been shown in experimental animals to protect against liver injury induced by carbon tetrachloride (5), alcohol (6), ischaemia/reperfusion (7), Fas (8), concanavalin A (9), haemorrhagic shock (10) and following liver transplantation, including that involving steatotic donor organs (11,12).”
BackgroundGraf, D., Kohlmann, C., Haselow, K., Gehrmann, T., Bode, J. G., & Häussinger, D. (2006) · Hepatology · doi:10.1002/hep.21368 · Cited by 32 · see citing works
Hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) infections in alcoholics.
Prakash, O., Mason, A., Luftig, R., & Bautista, A. (2002) · Frontiers in Bioscience · doi:10.2741/prakash · Cited by 32 · see citing works
“A recent study suggested that IL-6 in alcoholic liver disease was involved in mediating anti-apoptotic signals to overcome alcohol-induced hepatic apoptosis (126).”
BackgroundYuan, F., Chen, X.-P., Liu, J., Feng, W.-K., Cai, L., Wu, X.-Y., & Chen, S.-Y. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.10.020 · Cited by 31 · see citing works
“…have shown that multiple signaling pathways are involved in ethanol-induced apoptosis, including Seven in absentia homolog1 (Siah1) (Sun et al., 2014b; Yuan et al., 2016); p53 pathways (Yuan et al., 2016; Jana et al., 2010), MAPK signaling (Morio et al., 2013) and Bcl-2 family (Hong et al., 2002).”
Kamkar, M. M. A., Ahmad, R., Alsmadi, O., & Behbehani, K. (2014) · Journal of Diabetes and Metabolic Disorders · doi:10.1186/2251-6581-13-57 · Cited by 30 · see citing works
“The oncogenic role of constitutively activated STAT-3 is driven through the up-regulation of cell survival proteins (Bcl-xL, BCL-2) and cell cycle regulators (c-Myc, cyclin D) [38,40-42].”
BackgroundMicroarray gene analysis of the liver in a rat model of chronic, voluntary alcohol intake.
Deaciuc, I., Peng, X., D'Souza, N., Shedlofsky, S., Burikhanov, R., Voskresensky, I. V., & de Villiers, W. D. (2004) · Alcohol · doi:10.1016/j.alcohol.2003.12.001 · Cited by 30 · see citing works
“Thus, quantification of mRNA for genes encoding enzymes of alcohol metabolism (Morimoto et al., 1993; Ronis et al., 1993), cell signaling proteins (Gordon et al., 1986; Hong et al., 2002; Mochly-Rosen et al., 1988), apoptosis adaptors/ regulators (Deaciuc et al., 1999; Koteish et al., 2002; Yacoub et al., 1995), cell…”
Molecular and genetic association of interleukin-6 in tacrine-induced hepatotoxicity
Carr, D. F., Alfirevic, A., Tugwood, J. D., Barratt, B. J., Sherwood, J. L., Smith, J. M., Pirmohamed, M., & Park, B. K. (2007) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0b013e3282f00919 · Cited by 30 · see citing works
Stärkel, P., Saeger, C. D., Leclercq, I. A., Strain, A. J., & Horsmans, Y. (2005) · Journal of Hepatology · doi:10.1016/j.jhep.2005.03.024 · Cited by 28 · see citing works
Apoptotic gene expression in Paget's disease: a possible role for Bcl‐2
Brandwood, C. P., Hoyland, J., Hillarby, M., Berry, J., Davies, M., Selby, P., & Mee, A. (2003) · Journal of Pathology · doi:10.1002/path.1463 · Cited by 29 · see citing works
“Furthermore, interleukin-6 (IL-6) levels are raised in Pagetic osteoclasts and IL-6 is a known inducer of Bcl-2 [26,27].”
BackgroundShinoda, M., Tilles, A., Kobayashi, N., Wakabayashi, G., Takayanagi, A., Totsugawa, T., Harada, H., Obara, H., Suganuma, K., Berthiaume, F., et al. (2007) · Journal of Surgical Research · doi:10.1016/j.jss.2006.08.009 · Cited by 29 · see citing works
Stärkel, P., Schnabl, B., Leclercq, S., Komuta, M., Bataller, R., Argemí, J., Palma, E., Chokshi, S., Hellerbrand, C., Maccioni, L., et al. (2019) · Hepatology Communications · doi:10.1002/hep4.1364 · Cited by 28 · see citing works
“(33-35) Also, the absence of IL-6 in mice chronically exposed to alcohol promotes liver damage.(36-38) Stat3 likely acts differently depending on the cell type and the environment.”
BackgroundThe Role of Cytokines in the Pathogenesis and Treatment of Alcoholic Liver Disease
Scarlata, G. G. M., Colaci, C., Scarcella, M., Dallio, M., Federico, A., Boccuto, L., & Abenavoli, L. (2024) · Diseases · doi:10.3390/diseases12040069 · Cited by 27 · see citing works
“Some studies have shown how IL-6 expression can reduce apoptosis in hepatocytes and lead to mitochondrial DNA repair [85].”
BackgroundDumitru, A., Matei, E., Cozaru, G., Chisoi, A., Alexandrescu, L., Popescu, R., Butcaru, M. P., Dumitru, E., Rugină, S., & Tocia, C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052472 · Cited by 27 · see citing works
“IL-6 protects against apoptosis [92], reducing alcoholic liver injury and inflammation [93], and has a protective effect in the ALD early phase [94].”
BackgroundMechanisms of the inflammatory reaction implicated in alcoholic hepatitis: 2011 update.
Voican, C., Perlemuter, G., & Naveau, S. (2011) · Clinics And Research in Hepatology and Gastroenterology · doi:10.1016/j.clinre.2011.01.017 · Cited by 27 · see citing works
Pathophysiological Changes During Ischemia-reperfusion Injury in Rodent Hepatic Steatosis
Neri, A.-A., Dontas, I. A., Iliopoulos, D., & Karatzas, T. (2020) · In Vivo · doi:10.21873/invivo.11863 · Cited by 24 · see citing works
Hepatic ILC2 activity is regulated by liver inflammation-induced cytokines and effector CD4+ T cells
Steinmann, S., Schoedsack, M., Heinrich, F., Breda, P., Ochel, A., Tiegs, G., & Neumann, K. (2020) · Scientific Reports · doi:10.1038/s41598-020-57985-w · Cited by 26 · see citing works
Gavito, A., Bautista, D., Suárez, J., Badran, S., Arco, R., Pavón, F. J., Serrano, A., Rivera, P., Decara, J. M., Cuesta, A. L., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0157956 · Cited by 28 · see citing works
“These beneficial effects were attributed in part to the ability of IL-6 to mediate mitochondrial beta-oxidation of fatty acids, increase the hepatic export of triglycerides and cholesterol, and to its antioxidant, anti-apoptotic effects on hepatocytes [10, 17, 18, 21].”
BackgroundAlcoholic hepatitis: The pivotal role of Kupffer cells.
Suraweera, D., Weeratunga, A. N., Hu, R., Pandol, S., & Hu, R. (2015) · World Journal of Gastrointestinal Pathophysiology · doi:10.4291/wjgp.v6.i4.90 · Cited by 26 · see citing works
- Authors
- Hong, F., Kim, W.-H., Tian, Z., Jaruga, B., Ishac, E., Shen, X., & Gao, B.
- Affiliations
- National Institutes of Health (US)
- University of Science and Technology of China (CN)
- Virginia Commonwealth University (US)
- Corresponding author
- Gao, Bin
- Venue
- Oncogene
- Published
- 2002-01-03
- Volume
- 21
- Issue
- 1
- Pages
- 32-43
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2057210516
- Cited by
- 179
- References
- 0
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 4 · 2022: 4 · 2021: 8 · 2020: 10 · 2019: 7 · 2018: 7 · 2017: 10 · 2016: 8 · 2015: 6 · 2014: 6 · 2013: 7 · 2012: 11
- FWCI
- 7.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01aa012637-03)
- National Institute on Alcohol Abuse and Alcoholism (R01 AA 12637)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- interleukin-6, ethanol consumption, alcoholic liver disease, hepatocyte apoptosis, Bcl-2, Bcl-xL, Bax, TNF-α, anti-apoptotic signaling, IL-6 knockout mice
- MeSH terms
- Ethanol, Alcoholism, Animals, Body Weight, Cells, Cultured, Gene Expression Regulation, Genotype, Humans, Liver, Liver Diseases, Alcoholic, Male, Organ Size, Tumor Necrosis Factor-alpha, Interleukin-6, Apoptosis, Mice, Knockout, Proto-Oncogene Proteins c-bcl-2, Genes, bcl-2, Genetic Predisposition to Disease, Hepatocytes, bcl-X Protein, Mice
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