{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T22:10:34Z","timestamp":1761862234255,"version":"3.37.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2002,10,1]],"date-time":"2002-10-01T00:00:00Z","timestamp":1033430400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2003,12,30]],"date-time":"2003-12-30T00:00:00Z","timestamp":1072742400000},"content-version":"vor","delay-in-days":455,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,10]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>In murine models, overexpression of interleukin (IL)-12 and interferon (IFN)-\u03b3 can induce severe liver damage, whereas IL-10 has anti-inflammatory and hepatoprotective properties. To analyze the potential role of these cytokines in human fulminant hepatitis B, we used immunohistochemistry to study expression of IL-12, IFN-\u03b3, and IL-10 in explant livers of 11 patients with fulminant hepatitis B, 5 patients with fulminant hepatitis due to other etiologies, 37 patients with chronic liver disease (CLD; hepatitis B virus, n = 15; hepatitis C virus, n = 10; primary biliary cirrhosis, n = 12), and 10 normal controls (NCs). Furthermore, cytokine messenger RNA (mRNA) levels were determined in the liver specimens by quantitative real-time polymerase chain reaction (PCR). In NCs, faint IL-12 expression was detected in only a few Kupffer cells, whereas sinusoidal endothelial cells, hepatic stellate cells, bile ducts, and lymphocytes expressed IL-12 in CLD and, more conspicuously, in fulminant hepatitis B. In contrast, expression of IFN-\u03b3 and IL-10 was restricted to lymphocytes and Kupffer cells, respectively. In fulminant hepatitis B, numbers of IL-12- and IFN-\u03b3-positive cells markedly exceeded those found in CLD and NCs. A close correlation existed between IL-12 and IFN-\u03b3 expression (<jats:italic toggle=\"yes\">r<\/jats:italic> = 0.68; <jats:italic toggle=\"yes\">P<\/jats:italic> &lt; .001). In contrast, IL-10 expression was not significantly different in CLD and fulminant hepatitis. The quantitative differences in immunohistologic cytokine expression closely corresponded to the mRNA levels. In conclusion, our data indicate massive induction of the proinflammatory cytokines IL-12 and IFN-\u03b3 in fulminant hepatitis B, which is apparently not counterbalanced by the anti-inflammatory cytokine IL-10. This cytokine imbalance may play an important role in promoting inflammatory reactions leading to massive liver damage in fulminant hepatitis B.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1053\/jhep.2002.35532","type":"journal-article","created":{"date-parts":[[2003,3,26]],"date-time":"2003-03-26T02:15:53Z","timestamp":1048644953000},"page":"1001-1008","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":66,"title":["Imbalanced intrahepatic expression of interleukin 12, interferon gamma, and interleukin 10 in fulminant hepatitis B"],"prefix":"10.1097","volume":"36","author":[{"given":"Ludger","family":"Leifeld","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Ramakers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franz-Ludwig","family":"Dumoulin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Trautwein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tilman","family":"Sauerbruch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich","family":"Spengler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"10.1053\/jhep.2002.35532-BIB1|cit1","first-page":"457","article-title":"Interleukin-12-induced adhesion molecule expression in murine liver","volume":"152","author":"Myers","year":"1998","journal-title":"Am J Pathol"},{"key":"10.1053\/jhep.2002.35532-BIB2|cit2","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1093\/intimm\/6.1.157","article-title":"Administration of recombinant IL-12 to normal mice enhances cytolytic lymphocyte activity and induces production of IFN-gamma in vivo","volume":"6","author":"Gately","year":"1994","journal-title":"Int Immunol"},{"key":"10.1053\/jhep.2002.35532-BIB3|cit3","first-page":"1196","article-title":"Interleukin 12 augments the liver-associated immunity and reduces liver metastases","volume":"43","author":"Okuno","year":"1996","journal-title":"Hepatogastroenterology"},{"key":"10.1053\/jhep.2002.35532-BIB4|cit4","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1053\/jhep.2000.17701","article-title":"Murine concanavalin A-induced hepatitis is prevented by interleukin 12 (IL-12) antibody and exacerbated by exogenous IL-12 through an interferon-gamma-dependent mechanism","volume":"32","author":"Nicoletti","year":"2000","journal-title":"Hepatology"},{"key":"10.1053\/jhep.2002.35532-BIB5|cit5","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1093\/intimm\/8.4.569","article-title":"A pivotal role of IL-12 in Th1-dependent mouse liver injury","volume":"8","author":"Tanaka","year":"1996","journal-title":"Int Immunol"},{"key":"10.1053\/jhep.2002.35532-BIB6|cit6","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1084\/jem.178.5.1541","article-title":"Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis","volume":"178","author":"Ando","year":"1993","journal-title":"J Exp Med"},{"key":"10.1053\/jhep.2002.35532-BIB7|cit7","doi-asserted-by":"crossref","first-page":"956","DOI":"10.4049\/jimmunol.165.2.956","article-title":"Indispensable role for TNF-alpha and IFN-gamma at the effector phase of liver injury mediated by Th1 cells specific to hepatitis B virus surface antigen","volume":"165","author":"Ohta","year":"2000","journal-title":"J Immunol"},{"key":"10.1053\/jhep.2002.35532-BIB8|cit8","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1053\/gast.1996.v111.pm8690213","article-title":"Interferon gamma plays a critical role in T cell-dependent liver injury in mice initiated by concanavalin A","volume":"111","author":"Kusters","year":"1996","journal-title":"Gastroenterology"},{"key":"10.1053\/jhep.2002.35532-BIB9|cit9","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1006\/cyto.1999.0561","article-title":"Essential pathogenetic role for interferon (IFN-)gamma in concanavalin A-induced T cell-dependent hepatitis: exacerbation by exogenous IFN-gamma and prevention by IFN-gamma receptor-immunoglobulin fusion protein","volume":"12","author":"Nicoletti","year":"2000","journal-title":"Cytokine"},{"key":"10.1053\/jhep.2002.35532-BIB10|cit10","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1002\/hep.510250614","article-title":"Production and role of interleukin-10 in concanavalin A-induced hepatitis in mice","volume":"25","author":"Louis","year":"1997","journal-title":"Hepatology"},{"key":"10.1053\/jhep.2002.35532-BIB11|cit11","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3109\/08916939908994050","article-title":"Concanavalin A-induced hepatitis in mice is prevented by interleukin (IL)-10 and exacerbated by endogenous IL-10 deficiency","volume":"31","author":"Di Marco","year":"1999","journal-title":"Autoimmunity"},{"key":"10.1053\/jhep.2002.35532-BIB12|cit12","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/S1386-6346(00)00137-6","article-title":"Involvement of IL-10, an anti-inflammatory cytokine in murine liver injury induced by concanavalin A","volume":"20","author":"Kato","year":"2001","journal-title":"Hepatol Res"},{"key":"10.1053\/jhep.2002.35532-BIB13|cit13","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1053\/gast.1997.v112.pm9041256","article-title":"Hepatoprotective role of interleukin 10 in galactosamine\/lipopolysaccharide mouse liver injury","volume":"112","author":"Louis","year":"1997","journal-title":"Gastroenterology"},{"key":"10.1053\/jhep.2002.35532-BIB14|cit14","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1053\/gast.1996.v111.pm8780580","article-title":"Interleukin 10 reduces lethality and hepatic injury induced by lipopolysaccharide in galactosamine-sensitized mice","volume":"111","author":"Santucci","year":"1996","journal-title":"Gastroenterology"},{"key":"10.1053\/jhep.2002.35532-BIB15|cit15","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/S0168-8278(99)80282-7","article-title":"Interleukin-10 inhibits hepatic injury and tumor necrosis factor-alpha and interferon-gamma mRNA expression induced by staphylococcal enterotoxin B or lipopolysaccharide in galactosamine-sensitized mice","volume":"31","author":"Nagaki","year":"1999","journal-title":"J Hepatol"},{"key":"10.1053\/jhep.2002.35532-BIB16|cit16","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/0016-5085(89)90081-4","article-title":"Early indicators of prognosis in fulminant hepatic failure","volume":"97","author":"O'Grady","year":"1989","journal-title":"Gastroenterology"},{"key":"10.1053\/jhep.2002.35532-BIB17|cit17","doi-asserted-by":"crossref","first-page":"6014","DOI":"10.4049\/jimmunol.161.11.6014","article-title":"Recruitment of hepatic NK cells by IL-12 is dependent on IFN-gamma and VCAM-1 and is rapidly down-regulated by a mechanism involving T cells and expression of Fas","volume":"161","author":"Fogler","year":"1998","journal-title":"J Immunol"},{"key":"10.1053\/jhep.2002.35532-BIB18|cit18","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1093\/intimm\/11.5.657","article-title":"IL-12 induces specific cytotoxicity against regenerating hepatocytes in vivo","volume":"11","author":"Matsushita","year":"1999","journal-title":"Int Immunol"},{"key":"10.1053\/jhep.2002.35532-BIB19|cit19","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1172\/JCI7501","article-title":"IL-12-induced IFN-gamma is dependent on caspase-1 processing of the IL-18 precursor","volume":"104","author":"Fantuzzi","year":"1999","journal-title":"J Clin Invest"},{"key":"10.1053\/jhep.2002.35532-BIB20|cit20","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1006\/bbrc.1994.1122","article-title":"IFN-gamma induces IL-12 mRNA expression by a murine macrophage cell line, J774","volume":"198","author":"Yoshida","year":"1994","journal-title":"Biochem Biophys Res Commun"},{"key":"10.1053\/jhep.2002.35532-BIB21|cit21","first-page":"89","article-title":"Increased expression of interleukin-6 and tumor necrosis factor-alpha in pathologic biliary epithelial cells: in situ and culture study","volume":"78","author":"Yasoshima","year":"1998","journal-title":"Lab Invest"},{"key":"10.1053\/jhep.2002.35532-BIB22|cit22","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1053\/gast.1997.v112.pm9178702","article-title":"Bile ducts and portal and central veins are major producers of tumor necrosis factor alpha in regenerating rat liver","volume":"112","author":"Loffreda","year":"1997","journal-title":"Gastroenterology"},{"key":"10.1053\/jhep.2002.35532-BIB23|cit23","first-page":"372","article-title":"Promotion of leukocyte transendothelial cell migration by chemokines derived from human biliary epithelial cells in vitro","volume":"109","author":"Morland","year":"1997","journal-title":"Proc Assoc Am Physicians"},{"key":"10.1053\/jhep.2002.35532-BIB24|cit24","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1002\/1096-9896(2000)9999:9999<::AID-PATH725>3.0.CO;2-P","article-title":"Monocyte chemotactic protein-1, -2, and -3 are distinctively expressed in portal tracts and granulomata in primary biliary cirrhosis: implications for pathogenesis","volume":"193","author":"Tsuneyama","year":"2001","journal-title":"J Pathol"},{"key":"10.1053\/jhep.2002.35532-BIB25|cit25","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1016\/S0002-9440(10)65427-2","article-title":"Enhanced expression of CD80 (B7-1), CD86 (B7-2), and CD40 and their ligands CD28 and CD154 in fulminant hepatic failure","volume":"154","author":"Leifeld","year":"1999","journal-title":"Am J Pathol"},{"key":"10.1053\/jhep.2002.35532-BIB26|cit26","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/S0016-5085(00)70134-X","article-title":"Interleukin 10 treatment reduces fibrosis in patients with chronic hepatitis C: a pilot trial of interferon nonresponders","volume":"118","author":"Nelson","year":"2000","journal-title":"Gastroenterology"},{"key":"10.1053\/jhep.2002.35532-BIB27|cit27","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/0168-8278(95)80433-1","article-title":"Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge","volume":"22","author":"Knolle","year":"1995","journal-title":"J Hepatol"},{"key":"10.1053\/jhep.2002.35532-BIB28|cit28","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1016\/S0016-5085(99)70508-1","article-title":"Induction of cytokine production in naive CD4(+) T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells","volume":"116","author":"Knolle","year":"1999","journal-title":"Gastroenterology"},{"key":"10.1053\/jhep.2002.35532-BIB29|cit29","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1002\/hep.510280611","article-title":"Primary rat and mouse hepatic stellate cells express the macrophage inhibitor cytokine interleukin-10 during the course of activation in vitro","volume":"28","author":"Thompson","year":"1998","journal-title":"Hepatology"},{"key":"10.1053\/jhep.2002.35532-BIB30|cit30","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1074\/jbc.273.1.302","article-title":"Expression of interleukin-10 by in vitro and in vivo activated hepatic stellate cells","volume":"273","author":"Wang","year":"1998","journal-title":"J Biol Chem"},{"key":"10.1053\/jhep.2002.35532-BIB31|cit31","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1086\/517446","article-title":"Induction of interleukin-12 production in chronic hepatitis C virus infection correlates with the hepatocellular damage","volume":"178","author":"Quiroga","year":"1998","journal-title":"J Infect Dis"},{"key":"10.1053\/jhep.2002.35532-BIB32|cit32","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/S0168-8278(98)80226-2","article-title":"Increased interleukin-12 serum levels in chronic alcoholism","volume":"28","author":"Laso","year":"1998","journal-title":"J Hepatol"},{"key":"10.1053\/jhep.2002.35532-BIB33|cit33","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3346\/jkms.1999.14.2.175","article-title":"Expression of Th1 and Th2 type cytokines responding to HBsAg and HBxAg in chronic hepatitis B patients","volume":"14","author":"Lee","year":"1999","journal-title":"J Korean Med Sci"},{"key":"10.1053\/jhep.2002.35532-BIB34|cit34","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/S0168-8278(99)80334-1","article-title":"Elevated intracellular IFN-gamma levels in circulating CD8+ lymphocytes in patients with fulminant hepatitis","volume":"31","author":"Kimura","year":"1999","journal-title":"J Hepatol"},{"key":"10.1053\/jhep.2002.35532-BIB35|cit35","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1006\/viro.1999.9833","article-title":"Virus-specific lymphokine production differs quantitatively but not qualitatively in acute and chronic hepatitis B infection","volume":"261","author":"Jung","year":"1999","journal-title":"Virology"},{"key":"10.1053\/jhep.2002.35532-BIB36|cit36","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1086\/315826","article-title":"High levels of serum interleukin-10 and tumor necrosis factor-alpha are associated with fatality in fulminant hepatitis","volume":"182","author":"Nagaki","year":"2000","journal-title":"J Infect Dis"},{"key":"10.1053\/jhep.2002.35532-BIB37|cit37","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1002\/path.903","article-title":"Intrahepatic MxA expression in correlation to interferon-a expression in chronic and fulminant hepatitis","volume":"194","author":"Leifeld","year":"2001","journal-title":"J Pathol"},{"key":"10.1053\/jhep.2002.35532-BIB38|cit38","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1053\/gast.2000.9364","article-title":"Tumor necrosis factor alpha in the pathogenesis of human and murine fulminant hepatic failure","volume":"119","author":"Streetz","year":"2000","journal-title":"Gastroenterology"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1053%2Fjhep.2002.35532","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1053%2Fjhep.2002.35532","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-200210000-00028","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T15:56:16Z","timestamp":1738943776000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-200210000-00028"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,10]]},"references-count":38,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2002]]}},"URL":"https:\/\/doi.org\/10.1053\/jhep.2002.35532","relation":{},"ISSN":["0270-9139"],"issn-type":[{"type":"print","value":"0270-9139"}],"subject":[],"published":{"date-parts":[[2002,10]]}}}