Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model
Alcoholic hepatitis (AH) is associated with cytokeratin 8 and 18 (CK8/18) accumulation as cytoplasmic inclusion bodies, termed Mallory bodies (MBs). Studies with MB mouse models and cultured hepatocytes suggested that CK8/18 hyperphosphorylation might be involved in MB formation. However, no data ex...
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| Veröffentlicht in: | The American journal of pathology 2000, Vol.156 (1), p.77-90 |
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| creator | Stumptner, Conny Omary, M. Bishr Fickert, Peter Denk, Helmut Zatloukal, Kurt |
| description | Alcoholic hepatitis (AH) is associated with cytokeratin 8 and 18 (CK8/18) accumulation as cytoplasmic inclusion bodies, termed Mallory bodies (MBs). Studies with MB mouse models and cultured hepatocytes suggested that CK8/18 hyperphosphorylation might be involved in MB formation. However, no data exist on phosphorylation of CK8/18 in human AH. In this study, antibodies that selectively recognize phosphorylated epitopes of CK8 or CK18 were used to analyze CK8/18 phosphorylation states in normal human and murine livers, human AH biopsies, and livers of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-intoxicated mice, the last serving as model for MB induction. Hepatocyte cytokeratins become hyperphosphorylated at multiple sites in AH and in DDC-intoxicated mice. Hyperphosphorylation of CK8/18 occurred rapidly, after 1 day of DDC intoxication and preceded architectural changes of the cytoskeleton. In long-term DDC-intoxicated mice as well as in human AH, MBs preferentially contain hyperphosphorylated CK8/18 as compared with the cytoplasmic cytokeratin intermediate filament network suggesting that CK8/18 hyperphosphorylation may play a contributing role in MB pathogenesis. Furthermore, the site-specific phosphorylation of cytokeratin in different stages of MB induction provides indirect evidence for the involvement of a variety of protein kinases known to be activated in stress responses, mitosis, and apoptosis. |
| doi_str_mv | 10.1016/S0002-9440(10)64708-6 |
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Bishr ; Fickert, Peter ; Denk, Helmut ; Zatloukal, Kurt</creator><creatorcontrib>Stumptner, Conny ; Omary, M. Bishr ; Fickert, Peter ; Denk, Helmut ; Zatloukal, Kurt</creatorcontrib><description>Alcoholic hepatitis (AH) is associated with cytokeratin 8 and 18 (CK8/18) accumulation as cytoplasmic inclusion bodies, termed Mallory bodies (MBs). Studies with MB mouse models and cultured hepatocytes suggested that CK8/18 hyperphosphorylation might be involved in MB formation. However, no data exist on phosphorylation of CK8/18 in human AH. In this study, antibodies that selectively recognize phosphorylated epitopes of CK8 or CK18 were used to analyze CK8/18 phosphorylation states in normal human and murine livers, human AH biopsies, and livers of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-intoxicated mice, the last serving as model for MB induction. Hepatocyte cytokeratins become hyperphosphorylated at multiple sites in AH and in DDC-intoxicated mice. Hyperphosphorylation of CK8/18 occurred rapidly, after 1 day of DDC intoxication and preceded architectural changes of the cytoskeleton. In long-term DDC-intoxicated mice as well as in human AH, MBs preferentially contain hyperphosphorylated CK8/18 as compared with the cytoplasmic cytokeratin intermediate filament network suggesting that CK8/18 hyperphosphorylation may play a contributing role in MB pathogenesis. Furthermore, the site-specific phosphorylation of cytokeratin in different stages of MB induction provides indirect evidence for the involvement of a variety of protein kinases known to be activated in stress responses, mitosis, and apoptosis.</description><identifier>ISSN: 0002-9440</identifier><identifier>EISSN: 1525-2191</identifier><identifier>DOI: 10.1016/S0002-9440(10)64708-6</identifier><identifier>PMID: 10623656</identifier><identifier>CODEN: AJPAA4</identifier><language>eng</language><publisher>Bethesda, MD: Elsevier Inc</publisher><subject>Animals ; Biological and medical sciences ; Dicarbethoxydihydrocollidine - poisoning ; Gastroenterology. Liver. Pancreas. Abdomen ; Hepatitis, Alcoholic - metabolism ; Hepatitis, Alcoholic - pathology ; Humans ; Inclusion Bodies - metabolism ; Keratins - metabolism ; Liver - metabolism ; Liver - pathology ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Male ; Medical sciences ; Mice ; Other diseases. 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Bishr</creatorcontrib><creatorcontrib>Fickert, Peter</creatorcontrib><creatorcontrib>Denk, Helmut</creatorcontrib><creatorcontrib>Zatloukal, Kurt</creatorcontrib><title>Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model</title><title>The American journal of pathology</title><addtitle>Am J Pathol</addtitle><description>Alcoholic hepatitis (AH) is associated with cytokeratin 8 and 18 (CK8/18) accumulation as cytoplasmic inclusion bodies, termed Mallory bodies (MBs). Studies with MB mouse models and cultured hepatocytes suggested that CK8/18 hyperphosphorylation might be involved in MB formation. However, no data exist on phosphorylation of CK8/18 in human AH. In this study, antibodies that selectively recognize phosphorylated epitopes of CK8 or CK18 were used to analyze CK8/18 phosphorylation states in normal human and murine livers, human AH biopsies, and livers of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-intoxicated mice, the last serving as model for MB induction. Hepatocyte cytokeratins become hyperphosphorylated at multiple sites in AH and in DDC-intoxicated mice. Hyperphosphorylation of CK8/18 occurred rapidly, after 1 day of DDC intoxication and preceded architectural changes of the cytoskeleton. In long-term DDC-intoxicated mice as well as in human AH, MBs preferentially contain hyperphosphorylated CK8/18 as compared with the cytoplasmic cytokeratin intermediate filament network suggesting that CK8/18 hyperphosphorylation may play a contributing role in MB pathogenesis. Furthermore, the site-specific phosphorylation of cytokeratin in different stages of MB induction provides indirect evidence for the involvement of a variety of protein kinases known to be activated in stress responses, mitosis, and apoptosis.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Dicarbethoxydihydrocollidine - poisoning</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Hepatitis, Alcoholic - metabolism</subject><subject>Hepatitis, Alcoholic - pathology</subject><subject>Humans</subject><subject>Inclusion Bodies - metabolism</subject><subject>Keratins - metabolism</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Other diseases. 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Bishr</au><au>Fickert, Peter</au><au>Denk, Helmut</au><au>Zatloukal, Kurt</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model</atitle><jtitle>The American journal of pathology</jtitle><addtitle>Am J Pathol</addtitle><date>2000</date><risdate>2000</risdate><volume>156</volume><issue>1</issue><spage>77</spage><epage>90</epage><pages>77-90</pages><issn>0002-9440</issn><eissn>1525-2191</eissn><coden>AJPAA4</coden><abstract>Alcoholic hepatitis (AH) is associated with cytokeratin 8 and 18 (CK8/18) accumulation as cytoplasmic inclusion bodies, termed Mallory bodies (MBs). Studies with MB mouse models and cultured hepatocytes suggested that CK8/18 hyperphosphorylation might be involved in MB formation. However, no data exist on phosphorylation of CK8/18 in human AH. In this study, antibodies that selectively recognize phosphorylated epitopes of CK8 or CK18 were used to analyze CK8/18 phosphorylation states in normal human and murine livers, human AH biopsies, and livers of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-intoxicated mice, the last serving as model for MB induction. Hepatocyte cytokeratins become hyperphosphorylated at multiple sites in AH and in DDC-intoxicated mice. Hyperphosphorylation of CK8/18 occurred rapidly, after 1 day of DDC intoxication and preceded architectural changes of the cytoskeleton. In long-term DDC-intoxicated mice as well as in human AH, MBs preferentially contain hyperphosphorylated CK8/18 as compared with the cytoplasmic cytokeratin intermediate filament network suggesting that CK8/18 hyperphosphorylation may play a contributing role in MB pathogenesis. Furthermore, the site-specific phosphorylation of cytokeratin in different stages of MB induction provides indirect evidence for the involvement of a variety of protein kinases known to be activated in stress responses, mitosis, and apoptosis.</abstract><cop>Bethesda, MD</cop><pub>Elsevier Inc</pub><pmid>10623656</pmid><doi>10.1016/S0002-9440(10)64708-6</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological and medical sciences Dicarbethoxydihydrocollidine - poisoning Gastroenterology. Liver. Pancreas. Abdomen Hepatitis, Alcoholic - metabolism Hepatitis, Alcoholic - pathology Humans Inclusion Bodies - metabolism Keratins - metabolism Liver - metabolism Liver - pathology Liver. Biliary tract. Portal circulation. Exocrine pancreas Male Medical sciences Mice Other diseases. Semiology Phosphorylation Regular |
| title | Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model |
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