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Graft-versus-Host Disease–Related Cytokine-Driven Apoptosis Depends on p73 in Cytokeratin 15–Positive Target Cells  Qian Zhan, Robert Korngold, Cecilia.

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Presentation on theme: "Graft-versus-Host Disease–Related Cytokine-Driven Apoptosis Depends on p73 in Cytokeratin 15–Positive Target Cells  Qian Zhan, Robert Korngold, Cecilia."— Presentation transcript:

1 Graft-versus-Host Disease–Related Cytokine-Driven Apoptosis Depends on p73 in Cytokeratin 15–Positive Target Cells  Qian Zhan, Robert Korngold, Cecilia Lezcano, Frank McKeon, George F. Murphy  Biology of Blood and Marrow Transplantation  Volume 18, Issue 6, Pages (June 2012) DOI: /j.bbmt Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions

2 Figure 1 Association of p73 expression with K15+ stem cell domains of murine dorsal lingual mucosa. (A) Immunohistochemistry for K15 discloses discrete localization to stem cell regions at the tips and edges of the rete-like prominences (RLP). (B-D) RLP immunostained for K15 (B) are laser-microdissected (C and D) and mRNA-extracted for RT-PCR analysis. Intervening K15− zones of the basal layer are similarly removed. (E) Although p53 mRNA levels are expressed for both K15+ (blue) and K15− (red) laser-dissected basal cells, p73 is detected only within the K15+ microdomain. (F-H) By dual-labeling, p73+ nuclei are pink (mixture of blue nuclear staining and red p73 chromagen) (F) and are restricted to K15+ cells (G and H; green) at the tips of the RLP. DAPI-labeled nuclei are blue; omitted in H, and thus p73 appears red. The small red suprabasilar spots are extranuclear artifacts. Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions

3 Figure 2 Effect of short-term exposure to TNF-α/IL-1 in vitro. (A and B) Compared with 8 hours in medium alone (A) murine lingual explants exposed to TNF-α/Il-1 show prominent apoptosis in the vicinity of RLP tips by TUNEL staining (B, arrows). (C-E) Although these regions correspond to sites of p73 intranuclear expression (C, 8-hour exposure to medium; (D) 8-hour exposure to TNF-α/IL-1), p73 immunoreactivity patterns did not change with exposure to apoptosis-inducing cytokines, and by RT-PCR, mRNA levels also were not altered (E; a-c, K15+ regions laser captured from 3 explants exposed to medium [g, average]; d-f, K15+ regions laser captured from 3 explants exposed to cytokines [h, average]). (F) Human epidermis demonstrated a pattern of p73 distribution similar to the RLP, consistent with the established utility of the murine lingual model to study rete-associated stem cells. Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions

4 Figure 3 Dual staining for K15 and phosphorylated p73 (p73phos) and TUNEL and p73phos after exposure to TNF-α/IL-1 in vitro. Discrete regions of reactivity for p73phos (single arrows) are detected within the K15+ domains after cytokine but not medium exposure (K15, green; p73phos, red; upper 6 panels). Exposure to cytokines induces TUNEL-positive apoptosis (green; lower 4 panels) at the tips of RLP in intimate association with p73phos (red; double arrows). Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions

5 Figure 4 Correlation of p73 phos with early target cell injury in murine GVHD. DBA mice were exposed to lethal irradiation and engrafted with B10.D2 ATBM cells alone or in addition to CD4+ T cells. Tissues were sampled from both groups at a time point correlating with earliest target cell injury (day 7). In contrast to mice receiving the ATBM control inoculum (A) infiltration of the tips of RLP by CD4+ effector T cells (B) is seen only in mice receiving the CD4 effector inocula known to produce disease. At this juncture, and in contrast to controls (C) p73phos is observed within distorted and presumably dying cells at or near the sites of effector cell homing (D). Double labeling (bottom) confirms that CD4+ T cells are distinct from but focally in apposition to those cells expressing p73phos. Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions

6 Figure 5 Effect of TNF-α/IL-1 on murine lingual target cell apoptosis in lingual organ cultures from wild-type (WT) and p73−/− mice. Whereas WT mice showed TUNEL-positive cells within both the epithelial and subepithelial layers, p73−/− mice had TUNEL-positive cells only in the subepithelial region (upper panels, lower magnification; middle panels, higher magnification). The numbers of TUNEL-positive subepithelial cells were not statistically different between TNF-α/IL-1–exposed in WT and p73−/− explants (graph, upper right; P = .20). However, the numbers of epithelial TUNEL-positive cells in the RLP regions of WT explants significantly exceeded those in TNF-α/IL-1–exposed p73−/− animals (P = .016), which did not significantly differ from the rare TUNEL-positive epithelial apoptotic cells seen in WT and p73−/− explants exposed to medium alone (graph, lower right; P = .42). Biology of Blood and Marrow Transplantation  , DOI: ( /j.bbmt ) Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions

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