Interleukin-1 Receptor Antagonist Modulates the Early Phase of Liver Regeneration after Partial Hepatectomy in Mice
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{"title"=>"Interleukin-1 receptor antagonist modulates the early phase of liver regeneration after partial hepatectomy in mice", "type"=>"journal", "authors"=>[{"first_name"=>"Antonino", "last_name"=>"Sgroi", "scopus_author_id"=>"24776994300"}, {"first_name"=>"Carmen", "last_name"=>"Gonelle-Gispert", "scopus_author_id"=>"7801362435"}, {"first_name"=>"Philippe", "last_name"=>"Morel", "scopus_author_id"=>"36038296900"}, {"first_name"=>"Reto Marc", "last_name"=>"Baertschiger", "scopus_author_id"=>"8854153100"}, {"first_name"=>"Nadja", "last_name"=>"Niclauss", "scopus_author_id"=>"25947638500"}, {"first_name"=>"Gilles", "last_name"=>"Mentha", "scopus_author_id"=>"35227708200"}, {"first_name"=>"Pietro", "last_name"=>"Majno", "scopus_author_id"=>"56247786300"}, {"first_name"=>"Veronique", "last_name"=>"Serre-Beinier", "scopus_author_id"=>"6507334170"}, {"first_name"=>"Leo", "last_name"=>"Buhler", "scopus_author_id"=>"7007141710"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-80053197541", "pui"=>"362635659", "doi"=>"10.1371/journal.pone.0025442", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "sgr"=>"80053197541", "pmid"=>"21980458"}, "id"=>"8cf01ae6-ba88-359d-a7f7-048996c39d1c", "abstract"=>"BACKGROUND: Cytokine administration is a potential therapy for acute liver failure by reducing inflammatory responses and favour hepatocyte regeneration. The aim of this study was to evaluate the role of interleukin-1 receptor antagonist (IL-1ra) during liver regeneration and to study the effect of a recombinant human IL-1ra on liver regeneration.\\n\\nMETHODS: We performed 70%-hepatectomy in wild type (WT) mice, IL-1ra knock-out (KO) mice and in WT mice treated by anakinra. We analyzed liver regeneration at regular intervals by measuring the blood levels of cytokines, the hepatocyte proliferation by bromodeoxyuridin (BrdU) incorporation, proliferating cell nuclear antigen (PCNA) and Cyclin D1 expression. The effect of anakinra on hepatocyte proliferation was also tested in vitro using human hepatocytes.\\n\\nRESULTS: At 24h and at 48 h after hepatectomy, IL-1ra KO mice had significantly higher levels of pro-inflammatory cytokines (IL-6, IL-1β and MCP-1) and a reduced and delayed hepatocyte proliferation measured by BrdU incorporation, PCNA and Cyclin D1 protein levels, when compared to WT mice. IGFBP-1 and C/EBPβ expression was significantly decreased in IL-1ra KO compared to WT mice. WT mice treated with anakinra showed significantly decreased levels of IL-6 and significantly higher hepatocyte proliferation at 24h compared to untreated WT mice. In vitro, primary human hepatocytes treated with anakinra showed significantly higher proliferation at 24h compared to hepatocytes without treatment.\\n\\nCONCLUSION: IL1ra modulates the early phase of liver regeneration by decreasing the inflammatory stress and accelerating the entry of hepatocytes in proliferation. IL1ra might be a therapeutic target to improve hepatocyte proliferation.", "link"=>"http://www.mendeley.com/research/interleukin1-receptor-antagonist-modulates-early-phase-liver-regeneration-after-partial-hepatectomy-2", "reader_count"=>28, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Researcher"=>15, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>2, "Student > Master"=>4, "Student > Bachelor"=>1, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Researcher"=>15, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>2, "Student > Master"=>4, "Student > Bachelor"=>1, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>2, "Medicine and Dentistry"=>10, "Agricultural and Biological Sciences"=>14}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>10}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>14}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"United States"=>1, "Germany"=>1}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/731672"], "description"=>"<p>A) Primary human hepatocytes were isolated and cultured for 24 h before treatment with anakinra (10 µg/ml and 100 µg/ml). After 24 h, 48 h and 72 h proteins were extracted and whole cell lysats were subjected to western blotting. At 24 h, PCNA expression was significantly increased in hepatocytes treated with anakinra compared to non-treated hepatocytes. This difference is not observed at the other time points. The results are expressed as a ratio of PCNA expression by actin expression and are normalized in relation to none treated human hepatocytes. The quantification of bands of PCNA and actin were performed by densitometry. B) To study the cell viability, we performed a crystal violet assay. Human hepatocytes were first seeded at 100,000 cells/well in 500 µl culture medium in 24-well plates with or without adjunction of anakinra at 10 and 100 microgr/ml for 24h and viability was tested at 24, 48 and 72h. Our results showed that the cell viability was similar for all culture conditions (with or without anakinra) at various time points (n = 3). *  =  Statistical significance p<0.05. HH  =  primary human hepatocyte, PCNA  =  proliferating cell nuclear antigen.</p>", "links"=>[], "tags"=>["proliferation", "hepatocytes", "treated", "anakinra", "vitro"], "article_id"=>402016, "categories"=>["Physiology", "Biochemistry", "Chemistry", "Immunology"], "users"=>["Antonino Sgroi", "Carmen Gonelle-Gispert", "Philippe Morel", "Reto Marc Baertschiger", "Nadja Niclauss", "Gilles Mentha", "Pietro Majno", "Véronique Serre-Beinier", "Leo Buhler"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025442.g008", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Evaluation_of_proliferation_of_primary_human_hepatocytes_treated_by_anakinra_in_vitro_studies_/402016", "title"=>"Evaluation of proliferation of primary human hepatocytes treated by anakinra in vitro studies.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 14:25:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/731764"], "description"=>"<p>C/EBP α =  CAAT enhancer binding protein α, C/EBP β =  CAAT enhancer binding protein β, IGFBP-1 = Insulin-like growth factor binding protein 1, peroxisome proliferator-activated receptor-α.</p>", "links"=>[], "tags"=>["genes", "implicated"], "article_id"=>402117, "categories"=>["Physiology", "Biochemistry", "Chemistry", "Immunology"], "users"=>["Antonino Sgroi", "Carmen Gonelle-Gispert", "Philippe Morel", "Reto Marc Baertschiger", "Nadja Niclauss", "Gilles Mentha", "Pietro Majno", "Véronique Serre-Beinier", "Leo Buhler"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025442.t001", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Primers_of_genes_implicated_in_liver_regeneration_/402117", "title"=>"Primers of genes implicated in liver regeneration.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-20 14:26:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/730851"], "description"=>"<p>The evaluation of hepatocyte proliferation on native liver tissue was performed by analyzing BrdU incorporation by immunohistochemistry and by analyzing PCNA expression by western blot analysis at 24 h, 48 h, 72 h, 5 days and 7 days after 70% hepatectomy in WT mice and IL-1ra KO mice. (A) BrdU incorporation was significantly higher in WT mice compared to IL-1ra KO mice at 24 h and 48 h after 70% hepatectomy. The proliferation index of BrdU-stained tissue was determined at 200x magnification and labelled nuclei were counted in 5 randomly chosen fields, which approximate 1000 cells per section. Data were expressed as the percentage of BrdU-stained hepatocytes per total number of hepatocytes. Positive hepatocytes for BrdU incorporation are stained in brown. (Original magnification x200). (B) For WT mice, PCNA expression peaked at 48 h, in contrast for IL-1ra KO mice, the PCNA expression peaked at 72 h. The results are shown as a ratio of PCNA to actin expression. The quantification of signals of PCNA and actin are performed by densitometry. Scale bars  =  50 µm. *  =  Statistical significance p<0.05. D = day, WT = wild type, KO = knock-out, PCNA = proliferating cell nuclear antigen.</p>", "links"=>[], "tags"=>["regeneration", "il-1ra", "ko", "mice", "wt"], "article_id"=>401193, "categories"=>["Physiology", "Biochemistry", "Chemistry", "Immunology"], "users"=>["Antonino Sgroi", "Carmen Gonelle-Gispert", "Philippe Morel", "Reto Marc Baertschiger", "Nadja Niclauss", "Gilles Mentha", "Pietro Majno", "Véronique Serre-Beinier", "Leo Buhler"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025442.g001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Evaluation_of_liver_regeneration_in_IL_1ra_ko_mice_and_in_WT_mice_after_70_hepatectomy_/401193", "title"=>"Evaluation of liver regeneration in IL-1ra ko mice and in WT mice after 70% hepatectomy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 14:21:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/731486"], "description"=>"<p>The cytokines IL-6, MCP-1 and IL-1β were measured on peripheral blood of WT mice untreated or treated with two doses of anakinra (5mg/kg/d and 50mg/kg/d for 4 days) at 4 h, 24 h, 48 h and 72 h after partial hepatectomy. A) At 4 h post-hepatectomy, IL-6 levels increased significantly in the three groups of mice compared to levels before hepatectomy. However, the levels of IL-6 were significantly higher in untreated mice than in WT mice treated with anakinra at 4 h post-hepatectomy. However there was no difference between mice treated with 5mg/kg and those treated with 50mg/kg; B) the levels of MCP-1 were higher but did not reach statistical significance in mice treated with anakinra compared to untreated mice at 4 h post-hepatectomy; C) There was no difference in the levels of IL-1β between the three groups of mice. *  =  Statistical significance p<0.05. IL-6  =  Interleukin-6, MCP-1  =  monocyte chemotactic protein-1, IL-1β  =  Interleukin-1β, WT  =  wild type.</p>", "links"=>[], "tags"=>["regeneration", "wt", "mice", "treated", "anakinra"], "article_id"=>401834, "categories"=>["Physiology", "Biochemistry", "Chemistry", "Immunology"], "users"=>["Antonino Sgroi", "Carmen Gonelle-Gispert", "Philippe Morel", "Reto Marc Baertschiger", "Nadja Niclauss", "Gilles Mentha", "Pietro Majno", "Véronique Serre-Beinier", "Leo Buhler"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025442.g006", "stats"=>{"downloads"=>2, "page_views"=>61, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cytokine_profile_during_liver_regeneration_in_WT_mice_treated_by_anakinra_after_hepatectomy_/401834", "title"=>"Cytokine profile during liver regeneration in WT mice treated by anakinra after hepatectomy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 14:24:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/730982"], "description"=>"<p>IL-1ra, IL-1β, TNFα and HGF secretion were analyzed by ELISA. IL-6, MCP-1 were measured by a cytometric bead array mouse inflammation kit. These cytokines were measured on peripheral blood of WT mice and IL-1ra KO mice at 4 h, 24 h, 48 h, 72h, 5 days and 7 days after partial hepatectomy. A) The level of IL-1ra in WT mice showed a significant increase between 4 h and 48 h. As expected, in IL-1ra KO mice, IL-1ra was not detectable; B-D) the levels of IL-1β, IL-6 and MCP-1 were significantly higher in IL-1ra KO mice than in WT mice with a significant difference at 4 h post-hepatectomy; E-F) there were no differences in the levels of TNFα and HGF between the two groups of mice; *  =  Statistical significance p<0.05. D  =  day IL-1ra  =  Interleukin-1 receptor antagonist, IL-1β  =  Interleukin-1β, IL-6  =  Interleukin-6, MCP-1  =  monocyte chemotactic protein-1, TNFα  =  Tumor necrosis factor- α, HGF  =  Hepatocyte growth factor, WT  =  wild type, KO  =  knock-out.</p>", "links"=>[], "tags"=>["regeneration", "wt", "mice", "il-1ra", "ko"], "article_id"=>401327, "categories"=>["Physiology", "Biochemistry", "Chemistry", "Immunology"], "users"=>["Antonino Sgroi", "Carmen Gonelle-Gispert", "Philippe Morel", "Reto Marc Baertschiger", "Nadja Niclauss", "Gilles Mentha", "Pietro Majno", "Véronique Serre-Beinier", "Leo Buhler"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025442.g002", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cytokine_profile_during_liver_regeneration_in_WT_mice_and_in_IL_1ra_ko_mice_after_hepatectomy_/401327", "title"=>"Cytokine profile during liver regeneration in WT mice and in IL-1ra ko mice after hepatectomy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 14:22:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/731590"], "description"=>"<p>Alanine aminotransferase (ALT) was analyzed on peripheral blood of WT mice treated with anakinra (n = 3) compared to WT mice without treatment (n = 3). Our results showed that alanine aminotransferase increase at 4h after partial hepatectomy and returned to normal levels after 72h. The levels of alanine aminotransferase of WT mice without treatment was significantly higher at 24h after partial hepatectomy compared to mice treated with anakinra (5 or 50mg/kg). For treated mice, there was no difference for the protective effect of anakinra between 5 and 50mg/kg. *  =  Statistical significance p<0.05. WT  =  wild type.</p>", "links"=>[], "tags"=>["alanine"], "article_id"=>401942, "categories"=>["Physiology", "Biochemistry", "Chemistry", "Immunology"], "users"=>["Antonino Sgroi", "Carmen Gonelle-Gispert", "Philippe Morel", "Reto Marc Baertschiger", "Nadja Niclauss", "Gilles Mentha", "Pietro Majno", "Véronique Serre-Beinier", "Leo Buhler"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025442.g007", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Measurement_of_alanine_aminotransferase_/401942", "title"=>"Measurement of alanine aminotransferase.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 14:25:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/731136"], "description"=>"<p>Expression of cell cycle protein Cyclin D1 was analysed by western blot analysis on native liver tissue recovered at 24 h, 48 h, 72 h, 5 days and 7 days after 70% hepatectomy in WT and IL-1ra KO mice. A) Western blot of cyclin D1. The quantification of bands of Cyclin D1 and actin are performed by densitometry. B) Cyclin D1 is significantly higher in WT mice compared to IL-1ra KO mice at 24 h and 48 h after 70% hepatectomy. Cyclin D1 increased significantly at 24 h in WT mice, and in IL-1ra KO mice at 48 h after hepatectomy. The results are expressed as a ratio of Cyclin D1 expression by actin expression. The quantification of bands of Cyclin D1 and actin are performed by densitometry. *  =  Statistical significance p<0.05. D  =  day, WT  =  wild type, KO  =  knock-out .</p>", "links"=>[], "tags"=>["cyclin", "d1", "il-1ra", "ko", "mice", "wt", "points"], "article_id"=>401481, "categories"=>["Physiology", "Biochemistry", "Chemistry", "Immunology"], "users"=>["Antonino Sgroi", "Carmen Gonelle-Gispert", "Philippe Morel", "Reto Marc Baertschiger", "Nadja Niclauss", "Gilles Mentha", "Pietro Majno", "Véronique Serre-Beinier", "Leo Buhler"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025442.g003", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Analysis_of_Cyclin_D1_expression_in_IL_1ra_KO_mice_and_in_WT_at_early_time_points_after_hepatectomy_/401481", "title"=>"Analysis of Cyclin D1 expression in IL-1ra KO mice and in WT at early time points after hepatectomy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 14:22:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/731209"], "description"=>"<p>We analysed the expression of various genes implicated in liver regeneration (Bcl-xl, C/EBPα, C/EBPβ, c-myc, IGFBP-1 and PPARα) by real-time polymerase chain reaction at various time points 0 h, 4 h, 24 h, 48 h, 72 h post-hepatectomy. (A–H) Our results demonstrate that IGFBP-1 and C/EBPβ expression was significantly increased at 4 h in WT mice compared to IL-1ra KO (fold increase 59.1 vs. 15.3 for IGFBP-1 and 7.5 vs. 2.48 for C/EBPβ, respectively). Bcl-xl and c-myc expression was higher in WT mice but did not reach statistical significance. Expression level of C/EBPα and PPARα was similar. The fold increase was calculated for various time points and time 0 (0h) in control animals was used for normalization. *  =  Statistical significance p<0.05. WT  =  wild type, KO = knock-out, C/EBPα  =  CAAT enhancer binding protein α, C/EBPβ  =  CAAT enhancer binding protein β, IGFBP-1 =  Insulin-like growth factor binding protein 1, PPARα  =  Peroxisome proliferator-activated receptor alpha.</p>", "links"=>[], "tags"=>["genes"], "article_id"=>401562, "categories"=>["Physiology", "Biochemistry", "Chemistry", "Immunology"], "users"=>["Antonino Sgroi", "Carmen Gonelle-Gispert", "Philippe Morel", "Reto Marc Baertschiger", "Nadja Niclauss", "Gilles Mentha", "Pietro Majno", "Véronique Serre-Beinier", "Leo Buhler"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025442.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_genes_involved_in_liver_regeneration_/401562", "title"=>"Expression of genes involved in liver regeneration.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 14:23:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/731408"], "description"=>"<p>The evaluation of hepatocyte proliferation on native liver tissue was performed by analyzing BrdU incorporation by immunohistochemistry and by analyzing PCNA expression by western blot analysis at 24 h, 48 h, 72 h, 5 days and 7 days after 70% hepatectomy in untreated WT mice and groups of WT mice treated with anakinra (5mg/kg/d and 50mg/kg/d for 4 days). (A) BrdU incorporation was significantly higher in WT mice treated with anakinra at 50mg/kg compared to untreated mice at 24 h. At a 10 times lower dose (5mg/kg/d), BRDU incorporation was not different at 24 h in treated and untreated WT mice. At 48 h, the PCNA expression level was similar in all three groups of mice. The proliferation index of BrdU-stained tissue was determined at 200x magnification and labelled nuclei were counted in 5 randomly chosen fields, which approximately 1000 cells per section. Data were expressed as the percentage of BrdU-stained hepatocytes per total number of hepatocytes. Positive hepatocytes for BrdU incorporation are stained in brown. (Original magnification x200) (B) PCNA expression was significantly higher in WT mice treated with anakinra at a dose of 50mg/kg/d compared to untreated WT mice at 24 h after 70% hepatectomy. At a 10 times lower dose (5mg/kg/d), PCNA expression was not different at 24 h in treated and untreated WT mice. At 48 h, the PCNA expression level was similar in all three groups of mice. Scale bars  =  50 µm. *  =  Statistical significance p<0.05. WT = wild type, PCNA = proliferating cell nuclear antigen, BrdU = bromodeoxyuridine.</p>", "links"=>[], "tags"=>["regeneration", "mice", "treated", "anakinra"], "article_id"=>401755, "categories"=>["Physiology", "Biochemistry", "Chemistry", "Immunology"], "users"=>["Antonino Sgroi", "Carmen Gonelle-Gispert", "Philippe Morel", "Reto Marc Baertschiger", "Nadja Niclauss", "Gilles Mentha", "Pietro Majno", "Véronique Serre-Beinier", "Leo Buhler"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025442.g005", "stats"=>{"downloads"=>0, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Evaluation_of_liver_regeneration_in_mice_treated_by_anakinra_at_5mg_kg_d_and_at_50mg_kg_d_after_70_hepatectomy_/401755", "title"=>"Evaluation of liver regeneration in mice treated by anakinra at 5mg/kg/d and at 50mg/kg/d after 70% hepatectomy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 14:24:14"}

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