title: NK cells are biologic and biochemical targets of 6-mercaptopurine in Crohn's disease patients.
abstract: NK cells, which contribute to immune defense against certain viral infections and neoplasia, are emerging as modifiers of chronic immunologic diseases including transplant rejection and autoimmune diseases. Immunobiology and genetic studies have implicated NK cells as a modifier of Crohn's disease, a condition often treated with thiopurine agents such as 6-mercaptopurine (6-MP). Here, we demonstrate that thiopurines mediate NK cell apoptosis via a caspase 3 and 9 inclusive pathway, and that this process is triggered by thiopurine-mediated inhibition of Rac1. We also show that CD patients in clinical remission maintained on 6-MP have decreased NK cell Rac1 activity, and decreased NK cell numbers in their intestinal biopsies. These observations suggest that thiopurine targeting of NK cells may be a previously unappreciated therapeutic action of these agents in IBD.
authors.affiliation: Department of Pediatrics, Harbor UCLA Medical Center and Los Angeles Biomedical Institute, Torrance, CA, United States. Electronic address: syusung@labiomed.org.
authors.forename: Susy
authors.initials: S
authors.lastname: Yusung
authors.affiliation: Translational Genomics Group, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, and Medical Genetics Institute, Cedars Sinai Medical Center, Los Angeles, CA, United States.
authors.forename: Dermot
authors.initials: D
authors.lastname: McGovern
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.affiliation: Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hommes
authors.affiliation: Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
authors.forename: Venu
authors.initials: V
authors.lastname: Lagishetty
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Braun
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D003424:Crohn Disease / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism; D015122:Mercaptopurine / Q000627:therapeutic use*; D008875:Middle Aged; D055815:Young Adult; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D053148:Caspase 3; D053453:Caspase 9; D020830:rac1 GTP-Binding Protein
keywords: 6-Mercaptopurine; Caspase; Inflammatory bowel disease; NK cells; Rac1; Thiopurine