Section on Liver Biology, LPS, NIAAA
Bin Gao, MD., PhD, Chief
Research Interests
The primary interest of this group is the immunological aspects and molecular pathogenesis of liver diseases.
Hepatic inflammation and innate immunity
Alcohol consumption, nonalcoholic steatohepatitis, and viral hepatitis are three major causes of chronic liver injury leading to liver fibrosis, cirrhosis, and liver cancer. At present, the molecular and cellular mechanisms underlying liver injury and repair in these liver disorders are poorly understood. However, increasing evidence has suggested that immune cells play an important role in the pathogenesis of liver disease.
The hepatic immune system predominantly expresses innate immunity, whereby a large percentage of innate immune cells, including macrophages (ie, Kupffer cells), natural killer (NK) cells, and natural killer T (NKT) cells are involved. These cells are important as the first line of defense against infection and are poised to quickly respond to potential attacks by any pathogen in the absence of antigen recognition. Interestingly, in liver injury and repair, innate immunity is activated. Hence, our laboratory is investigating the immunologic mechanisms of liver injury and repair, focusing on innate immunity in liver disorders such as fatty liver and liver fibrosis, as well as in liver regeneration.
Our laboratory is also interested in studying the effects of cytokines in hepatic inflammation and innate immunity in liver diseases including alcoholic liver injury. In last several years, we investigated the roles of cytokines (IL-6, IL-22) and their downstream signals (STAT3) in the development and progression of fatty liver diseases, liver injury, and repair. We have identified that IL-6 plays an important role in protection against liver injury in several murine models of alcoholic liver injury, nonalcoholic fatty liver disease, fatty liver transplantation, and T cell hepatitis. Currently, we are exploring the role of STAT3 in these models by using STAT3 conditional knock out mice. We are also interested in studying the roles of other STATs in fatty liver, liver injury and repair.
Selected Publications
1. Horiguchi, N., Wang, L., Mukhopadhyay, P., Jeong, W., Lafdil, F., Osei-Hyiaman, D., Moh, A., Fu, X., Pacher, P., Kunos, G., Gao, B.: Cell-dependent pro- and anti-inflammatory role of STAT3 in alcoholic liver injury.
Gastroenterology 2008;134:1148-1158
2. Gao, B., Jeong, W., and Tian, Z.: Liver: an organ with predominant innate immunity (Review).
Hepatology 2008; 47:729-736
3. Kunos, G., and Gao, B.: Endocannabinoids, CB1 receptors, and liver disease – hitting more than one bird with the same stone (Invited Editorial Comment).
Gastroenterology, 2008;134:622-625
4. Jeong, W., Park, O., Gao, B.: Abrogation of anti-fibrotic effects of NK/IFN-g contributes to alcohol acceleration of liver fibrosis.
Gastroenterology 2008, 134:248-258
5. Hu, W., Ferris, S., Tweten, R., Wu, G., Radaeva, S., Gao, B., Bronson, R., Halperin, J., Qin, X.: Conditional, rapid and targeted ablation of cells expressing human CD59 in transgenic mice by intermedilysin.
Nature Medicine 2008;14, 98 – 103
6. Jeong, W., Osei-Hyiaman, D., Park, O., Liu, J., Bátkai, S., Mukhopadhyay, P., Horiguchi, N., Harvey-White, J., Marsicano, G., Lutz, B., Gao, B., Kunos, G.: Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic liver disease.
Cell Metabolism 2008; 7(3):227-35.
7. Chuang, Y., Lian, Z., Yang, G., Shu, S., Moritoki, Y., Ridgway, M., Kronenberg, M., Flavell, R., Gao, B., and Gershwin, E.: CD1d-restricted NKT cells exacerbate liver injury in a TGF-b receptor II dominant-negative mouse model of primary biliary cirrhosis.
Hepatology 2008;47:571-580
8. Radaeva, S., Wang, L., Radaev, S., Jeong, W., Park, O., and Gao, B.: Retinoic acid signaling upregulates natural killer cell activating ligand RAE1 in hepatic stellate cells.
Am. J. Physiol (GI and Liver) 2007, 293:G809-816.
9. Gao, B., Radaeva, S., Jeong, W.: Activation of NK cells inhibits liver fibrosis: A novel strategy to treat liver fibrosis (Invited review).
Expert Review of Gastroenterology and Hepatology 2007, 1:173-180
10. Batkai, S., Osei-Hyiaman, D., Pan, H., El-Assal, O., Rajesh M., Mukhopadhyay, P., Hong, F., Harvey-White, J., Jafi, A., Hasko, G., Huffman, J., Gao, B., Kunos, G., Pacher, P.: Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury.
FASEB J 2007, 21:1788-800
11. Cui, Y., Hosui, A., Sun, R., Shen, K., Gavrilova, O., Chen, W., Cam, M., Gao, B., Robinson, G., Hennighausen, L.: Inactivation of hepatic Stat5a/b results in aberrant GH-induced activation of Stat1 and Stat3, hepatosteatosis, and diminished liver regeneration.
Hepatology 2007;46:504-513
12. Mohanraj, R., Pan, H., Mukhopadhyay, P., Bátkai, S., Osei-Hyiaman, D., Hasko, G., Liaudet, L., Gao, B., and Pacher, P.: Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response and apoptosis.
J. Leuk. Biol. 2007, 82: 1382–1389
13. Sun R., Park, O., Horiguchi, N, Kulkarni, S., Jaruga, B., Jeong, W., Sun, H., Radaeva, S., and Gao, B:. STAT1 contributes to dsRNA inhibition of liver regeneration after partial hepatectomy in mice.
Hepatology 2006, 44:955-966
14. Jeong, W., Park, O., Radaeva, S., and Gao, B: STAT1 inhibits liver fibrosis through attenuating stellate cell activation and stimulating NK cell killing of activated stellate cells.
Hepatology 2006, 44:1441-1451
15. Radaeva, S., Sun, R., Jaruga, B., Nguyen, V., Tian, Z., Gao B.: Natural killer cells ameliorate liver fibrosis through killing activated stellate cells in RAE1/NKG2D- and TRAIL-dependent manners.
Gastroenterology 2006, 130: 435-452.
16. Li, B., Sun, R., Wei, H., Gao, B., and Tian, Z.: Interleukin-15 prevents Con-A induced liver injury via NKT-dependent mechanism.
Hepatology 2006, 43:1211-1219
17. Xu, X., Kobayashi, S., Qiao, W., Li, C., Xiao, C., Radaeva, S., Stiles, B., Wang, R., Ohara, N., Yoshino, T., LeRoith, D., Torbenson, M., Gores, G., Wu, H., Gao, B., and Deng, C. Induction of cholangiocellular carcinoma by liver specific disruption of Smad4 and Pten in mice.
J. Clin. Invest. 2006, 116(7):1843-1852
18. Kunos, G., Osei-Hyiaman, D., Bátkai, S., and Gao, B.: Cannabinoids hurt, heal in cirrhosis (News and Views).
Nature Medicine 2006, 12:608-610
19. Kim, W., Lee, J., Suh, Y., Hong, S., Choi, J., Lim, J., Song, J., Gao, B., and Jung, M.: Exposure to chronic high glucose induces b-cell apoptosis through decreased interaction of GCK with mitochondria: downregulation of GCK in pancreatic b cells.
Diabetes 2005,54:2602-11
20. Sun R., and Gao, B.: Negative regulation of liver regeneration by innate immunity (NK/IFN-g).
Gastroenterology 2004, 127, 1525-1539
21. Sun R., Tian, Z., Kulkarni, S., and Gao, B.: Interleukin-6 (IL-6) prevents T cell-mediated hepatitis: IL-6 inhibits NKT cells by CD4+ cells- and STAT3-dependent mechanisms.
J. Immunol. 2004 172:5648-5655
22. Radaeva, R., Sun, R., Pan, H., Hong, F., and Gao, B.: Interleukin-22 (IL-22) plays a protective role in T cell hepatitis: IL-22 is a survival factor for hepatocytes via activation of STAT3.
Hepatology 2004, 39(5):1332-1342.
23. Hong, F., Radaeva, S., Pan, H., Tian, Z., Veech, R., and Gao, B.: Interleukin-6 treatment alleviates steatosis and ischemia/reperfusion injury in mice with fatty liver disease.
Hepatology 2004, 40: 933-941.
24. Gao, B., Hong, F., and Radaeva, S: Host factors and interferon-a treatment failure in hepatitis C: molecular mechanisms and potential therapeutic improvement (Review).
Hepatology 2004, 39:880-890.
25. Radaeva, S., Jaruga, B., Kim, W., Heller, T., Liang, T., and Gao, B.: IFN-g treatment inhibits IFN-α-activated signaling in hepatic cells: Evidence for the involvement of STAT1 induction and hyperexpression of STAT1 in chronic hepatitis C.
Biochem. J. 2004 379: 199-208
26. Jaruga, B., Hong F., Kim, E., Sun, R., and Gao, B.: Chronic ethanol consumption potentiates liver injury in T-cell mediated hepatitis: Disregulation of STAT3 and NF-kB signals.
Am. J. Physiol (GI and Liver) 2004, 287:G471-G479
27. Jaruga, B., Kim, W., Hong, F., and Gao, B.: IFN-g/STAT1 acts as a pro-inflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines/adhesion molecules: A central role of IRF-1.
Am. J. Physiol (GI and Liver) 2004, 287:G1044-G1052
28. Jaruga, B., Hong, F., Sun, R., Radaeva, S., and Gao, B.: Crucial Role of IL-4/STAT6 in T cell-mediated hepatitis: Upregulating eotaxins and IL-5, and recruiting leukocytes.
J. Immunol. 2003, 171: 3233-3244
29. Kim, W., Hong, F., Radaeva, S., Jaruga, B., and Gao, B.: STAT1 plays an essential role in LPS/D-galactosamine-induced liver injury.
Am. J. Physiol (GI and Liver) 2003, 285:G761-768.
30. Liu, J., Batkai, S., Pacher, P., Harvey-White, J., Wagner, J.A., Cravatt, B.F., Gao, B., and Kunos, G.: LPS Induces anandamide synthesis in macrophages via CD14/MAPK/PI3K/ NF-kB independently of platelet activating factor.
J. Biol. Chem 2003, 278:45034-45039.
31. Sun, Z., Klein, A. S., Radaeva, S., Hong, F., El-Assal, O., Jaruga, B., Pan, H., Batkai, S., Tian, Z., Hoshino, S., Kunos, G., Diehl, A., and Gao, B.: In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats.
Gastroenterology 2003, 125:202-215.
32. Radaeva, S., Jaruga, B., Hong, F., Kim, W. H., Fan, S., Cai, H., Strom S., Liu, Y., El-Assal, O., and Gao, B.: Interferon-a activates multiple STAT signals and downregulates c-Met in primary human hepatocytes.
Gastroenterology 2002, 122:1020-1034.
33. Nguyen, V. N., and Gao, B.: Expression of interferon-a signaling components in human alcoholic liver disease.
Hepatology 2002, 35:425-432.
34. Hong, F., Kim, W. H., Tian, Z., Jaruga, B., Ishac, E., Shen, X., and Gao, B.: Elevated interleukin-6 during ethanol consumption acts as a potential endogenous protective cytokine against ethanol-induced apoptosis in the liver: involvement of Bcl-2 and Bcl-x(L) proteins.
Oncogene 2002, 21:32-43.
35. Hong, F., Jaruga, B., Kim, W. H., Radaeva, S., Tian, Z., El-Assal, O., Nguyen, V., and Gao, B.: Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS.
J. Clin. Invest. 2002, 110 (10): 1503-1513.
36. Liu, J., Tian, Z., Gao, B., and Kunos G.: Dose-dependent activation of antiapoptotic and proapoptotic pathways by ethanol treatment in human vascular endothelial cells: differential involvement of adenosine.
J. Biol. Chem. 2002, 277:20927-20933.
37. Kim, W. H., Hong, F., Jaruga, B., Hu, Z., Fan, S., Liang, J., and Gao, B.: Additive activation of nuclear factor-kB by ethanol, hepatitis B protein X and HCV core protein: Involvement of TNFa receptor 1-independent and –dependent mechanisms.
FASEB J. 2001, 15:2551-2553.
38. Hong, F., Nguyen, V. N., and Gao, B.: Tumor necrosis factor a attenuates interferon a/b signaling in the liver: involvement of SOCS3 and SHP2 and implication in resistance to interferon therapy.
FASEB J. 2001, 15:1595-1597
39. Tian, Z. G., Shen, X. N., Hong, F., and Gao, B.: IL-1 b attenuates interferon a/b-induced antiviral activity and STAT1 activation in the liver: involvement of proteasome-dependent mechanism.
J. Immunol. 2000, 165:3959-3965
40. Nguyen, V. A., Hong, F., Ishac, E., Chen, J., and Gao, B.: Interferons activate MAP kinase and STAT1 in freshly isolated rat liver cells: differential regulation by acute ethanol.
Biochem. J. 2000, 349:427-435
41. Shen, X. N., Tian, Z. G., Holtzman, M. J., and Gao, B.: Cross-talk between interleukin 1b (IL-1b) and IL-6 signaling pathways: IL-1b inhibits IL-6-activated STAT1 by a ubiquitin-proteasome dependent mechanism.
Biochem. J. 2000, 352:913-919
42. Liu, J., Shen, X., Nguyen, V. A., Kunos, G., and Gao, B.: a1 Adrenergic agonist induction of p21Waf1/cip1 mRNA stability in transfected HepG2 cells correlates with the increased binding of an AU-rich element binding factor.
J. Biol. Chem. 2000, 275:11846-11851
Updated: April 2008