Graft-versus-Host Disease-Related Cytokine-Driven Apoptosis Depends on p73 in Cytokeratin 15-Positive Target Cells

6Citations
Citations of this article
10Readers
Mendeley users who have this article in their library.

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. © 2012 American Society for Blood and Marrow Transplantation.

Cite

CITATION STYLE

APA

Zhan, Q., Korngold, R., Lezcano, C., McKeon, F., & Murphy, G. F. (2012). Graft-versus-Host Disease-Related Cytokine-Driven Apoptosis Depends on p73 in Cytokeratin 15-Positive Target Cells. Biology of Blood and Marrow Transplantation, 18(6), 841–851. https://doi.org/10.1016/j.bbmt.2012.02.004

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free