title: Regulation of the expression of chaperone gp96 in macrophages and dendritic cells.
abstract: The chaperone function of the ER-residing heat shock protein gp96 plays an important role in protein physiology and has additionally important immunological functions due to its peptide-binding capacity. Low amounts of gp96 stimulate immunity; high quantities induce tolerance by mechanisms not fully understood. A lack of gp96 protein in intestinal macrophages (IMACs) from Crohn`s disease (CD) patients correlates with loss of tolerance against the host gut flora, leading to chronic inflammation. Since gp96 shows dose-dependent direction of immunological reactions, we studied primary IMACs and developed cell models to understand the regulation of gp96 expression. Induction of gp96-expression was higher in in vitro differentiated dendritic cells (i.v.DCs) than in in vitro differentiated macrophages (i.v.MACs), whereas monocytes (MOs) expressed only low gp96 levels. The highest levels of expression were found in IMACs. Lipopolysaccharide (LPS), muramyl dipeptide (MDP), tumour necrosis factor (TNF), and Interleukin (IL)-4 induced gp96-expression, while IL12, IL-17, IL-23 and interferon (IFN)-γ were not effective indicating that Th1 and Th17 cells are probably not involved in the induction of gp96. Furthermore, gp96 was able to induce its own expression. The ER-stress inducer tunicamycin increased gp96-expression in a concentration- and time-dependent manner. Both ulcerative colitis (UC) and CD patients showed significantly elevated gp96 mRNA levels in intestinal biopsies which correlated positively with the degree of inflammation of the tissue. Since gp96 is highly expressed on the one hand upon stress induction as during inflammation and on the other hand possibly mediating tolerance, these results will help to understand the whether gp96 plays a role in the pathophysiology of inflammatory bowel disease (IBD).
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Lutz
authors.initials: L
authors.lastname: Wolfram
authors.forename: Anne
authors.initials: A
authors.lastname: Fischbeck
authors.forename: Isabelle
authors.initials: I
authors.lastname: Frey-Wagner
authors.forename: Kacper A
authors.initials: KA
authors.lastname: Wojtal
authors.forename: Silvia
authors.initials: S
authors.lastname: Lang
authors.forename: Michael
authors.initials: M
authors.lastname: Fried
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Vavricka
authors.forename: Martin
authors.initials: M
authors.lastname: Hausmann
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rogler
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D001706:Biopsy; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D015212:Inflammatory Bowel Diseases / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C053387:endoplasmin; D000119:Acetylmuramyl-Alanyl-Isoglutamine