NF-κB determines localization and features of cell death in epidermis
Cornelia S. Seitz, … , Kaede Hinata, Paul A. Khavari
Cornelia S. Seitz, … , Kaede Hinata, Paul A. Khavari
Published February 1, 2000
Citation Information: J Clin Invest. 2000;105(3):253-260. https://doi.org/10.1172/JCI7630.
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Article

NF-κB determines localization and features of cell death in epidermis

Abstract

Specialized forms of physiologic cell death lacking certain characteristic morphologic features of apoptosis occur in terminally differentiating tissues, such as in the outer cell layers of epidermis. In these cell layers, NF-κB translocates from the cytoplasm to the nucleus and induces target gene expression. In light of its potent role in regulating apoptotic cell death in other tissues, NF-κB activation in these cells suggests that this transcription factor regulates cell death during terminal differentiation. Here, we show that NF-κB protects normal epithelial cells from apoptosis induced by both TNFα and Fas, whereas NF-κB blockade enhances susceptibility to death via both pathways. Expression of IκBαM under control of keratin promoter in transgenic mice caused a blockade of NF-κB function in the epidermis and provoked premature spontaneous cell death with apoptotic features. In normal tissue, expression of the known NF-κB–regulated antiapoptotic factors, TRAF1, TRAF2, c-IAP1, and c-IAP2, is most pronounced in outer epidermis. In transgenic mice, NF-κB blockade suppressed this expression, whereas NF-κB activation augmented it, consistent with regulation of cell death by these NF-κB effector proteins. These data identify a new role for NF-κB in preventing premature apoptosis in cells committed to undergoing physiologic cell death and indicate that, in stratified epithelium, such cell death normally proceeds via a distinct pathway that is resistant to NF-κB and its antiapoptotic target effector genes.J. Clin. Invest.105:253–260 (2000).

Authors

Cornelia S. Seitz, Rachel A. Freiberg, Kaede Hinata, Paul A. Khavari

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NF-κB effects on expression of antiapoptotic genes in mice transgenic fo...
NF-κB effects on expression of antiapoptotic genes in mice transgenic for augmentation or loss of epidermal NF-κB function. (a–d) Immunofluorescence analysis of TRAF1, TRAF2, c-IAP1, and c-IAP2 in normal littermate control. (e–h) Immunofluorescence analysis in IκBαM[+] transgenic mice. (i–l) Immunofluorescence analysis in mice transgenic for constitutively active p50 NF-κB subunit; note relative hypoplasia of p50[+] epidermis. (m) Anti-rabbit secondary antibody alone control. Note decrease in detection of TRAF1, TRAF2, c-IAP1, and, to a lesser extent, c-IAP2 in IκBαM[+] epidermis, especially in the outer epithelial layers, compared with control. Note also the marked increase in TRAF1, TRAF2, c-IAP1, and, to a lesser extent, c-IAP2 expression, throughout epidermis of p50[+] skin, including cells all the way to the basal layer. The dashed line represents the epidermal basement membrane zone; all layers of epidermal morphology are highlighted in p50[+] skin. All micrographs are at the same magnification (bar = 50 μM, shown in a).