title: Graft-versus-host disease-related cytokine-driven apoptosis depends on p73 in cytokeratin 15-positive target cells.
abstract: Acute graft-versus-host disease (GVHD), a major complication of allogeneic stem cell transplantation, involves cytotoxic soluble and cellular effectors that selectively induce apoptosis in normally apoptosis-resistant, cytokeratin 15 (K15)-expressing epithelial stem cells residing at the tips of rete ridges of human epidermis and in analogous rete-like prominences (RLPs) of murine dorsal lingual epithelium. The mechanisms whereby epithelial stem cells are rendered vulnerable to apoptosis during allostimulation are unknown. We hypothesized that GVHD-induced target cell injury may be related to pathways involving the p53 family that are constitutively expressed by epithelial stem cells and designed to trigger physiological apoptosis as a result of environmental danger signals. Among the p53 family members, we found that p73 protein and mRNA were preferentially expressed in K15(+) RLPs of murine lingual squamous epithelium. On in vitro exposure to recombinant TNF-α and IL-1 in an organ culture model previously shown to replicate early GVHD-like target cell injury, apoptosis was selectively induced in K15(+) stem cell regions and was associated with induction of phosphorylated p73, a marker for p73 activation, and apoptosis was abrogated in target tissue obtained from p73-deficient (p73(-/-)) mice. Evaluation of early in vivo lesions in experimental murine GVHD disclosed identical patterns of phosphorylated p73 expression that coincided with the onset of effector T cell infiltration and target cell apoptosis within K15(+) RLPs. This study is the first to suggest that paradoxical apoptosis in GVHD of physiologically protected K15(+) epithelial stem cells is explainable, at least in part, by cytokine-induced activation of suicide pathways designed to eliminate stem cells after exposure to deleterious factors perceived to be harmful to the host.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhan
authors.forename: Robert
authors.initials: R
authors.lastname: Korngold
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lezcano
authors.forename: Frank
authors.initials: F
authors.lastname: McKeon
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D053569:Keratin-15 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology*; D009924:Organ Culture Techniques; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D012867:Skin / Q000166:cytology / Q000276:immunology; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000276:immunology; D014059:Tongue / Q000166:cytology / Q000276:immunology; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D004268:DNA-Binding Proteins; D007375:Interleukin-1; D053569:Keratin-15; D009687:Nuclear Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins