Добавил:
Upload Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз: Предмет: Файл:
Apoptosis_Physiology_and_Pathology.pdf
Скачиваний:
31
Добавлен:
12.02.2015
Размер:
10.82 Mб
Скачать

CELL DEATH IN THE SKIN

331

promotes upregulation of Fas in keratinocytes and thereby sensitizes them toward apoptosis. In addition, several data suggest a role for Fas/FasL as a positive regulator of pathological skin inflammation. Therefore, the mechanism of Fas/FasL signaling was investigated in reconstructed human epidermis. Surprisingly, these experiments indicated that FasL rather induced inflammation in reconstructed epidermis; this in contrast to monolayer keratinocyte cultures, in which FasL induced apoptosis. Unexpectedly, the epidermal growth factor receptor-ERK axis was found to be involved in the transcriptional inflammatory responses to FasL in the epidermis.

3.6. Graft-versus-host disease

Graft-versus-host disease (GVHD) can occur after allogeneic bone marrow transplantation and is the consequence of tissue damage induced by cytotoxic T cells. Acute and chronic GVHD are mainly manifested in the skin (cutaneous GVHD), the liver, and the gastrointestinal tract. Acute GVHD results in high mortality rates. Keratinocytes in cutaneous GVHD die by apoptosis mediated by FasL presented by the lymphocytes and secreted TNFα. In mice it was shown that the use of FasLand/or perforin-deficient T cells in transplantation experiments reduces mortality and manifestation of the cutaneous GVH reaction. Importantly, neutralizing both TNFα and FasL with antagonizing antibodies completely abrogates the disorder. Blocking Fas alone lowers mortality rates, as does TNF blocking. However, when bone marrow transplantation is used as a therapy, this approach to dampen GVHD cannot be used because the graft-versus-leukemia reaction is TNFdependent.

4. CONCLUDING REMARKS AND PERSPECTIVES

The skin is situated at the critical junction between the host and the environment and is subject to a variety of potentially damaging agents, including microbial organisms, toxins, and gene-damaging radiation. The maintenance of homeostatic conditions is crucial for the epidermal function. From this overview, it should be clear that proper control of apoptosis and inflammation during epidermal differentiation is of major importance in keeping the architectural integrity in check. Although terminal keratinocyte differentiation is a textbook example of programmed cell death, the apoptotic signaling cascade does not seem to be involved in epidermal differentiation leading to cornification.

The epidermal cells, such as keratinocytes and melanocytes, are the only cells of the body that are directly exposed to noxious UV irradiation. Several molecules involved in apoptotic signaling are required to remove cells with excessive UV-induced DNA damage. If not properly removed, these cells may become cancerous. Some members of the TNF superfamily, such as the death receptors and their ligands, play an essential role during epidermal development and homeostasis. The major consequence of death receptor signaling in the epidermis is apoptosis, inflammation, and the induction of developmental cues. The deregulation of death receptor signaling, such as signaling to apoptosis or NF-κB activation, is involved in the pathogenesis of certain cutaneous diseases. The loss of the ability of damaged cells to undergo apoptosis contributes to tumor development and progression, whereas excessive apoptosis can lead the development of necrolysis, GVHD, and possibly eczematous dermatitis. Interestingly, recent evidence suggests that Fas/FasL signaling can convert from apoptotic to inflammatory signaling in keratinocytes, depending on the cellular conditions. This implies that apoptosis could serve to restrict uncontrolled inflammation, even at the price of temporary tissue damage.

During the past decade, significant advances have been made in understanding cell death signaling in health and disease. This has led to the conceptualization and development of new therapeutic tools targeting these signaling pathways, some of which are already being used in the clinic or in clinical trials. In addition, a better understanding of the role of apoptosis in a number of cutaneous diseases will lead to the further development of improved treatment protocols for these pathologies.

ACKNOWLEDGMENTS

We thank A. Bredan for editing the manuscript. This research has been supported by Flanders Institute for Biotechnology (VIB) and several grants. European grants: FP6 ApopTrain, MRTN-CT-035624; EC RTD Integrated Project, FP6 Epistem, LSHB-CT-2005–019067; EC RTD Integrated Project, Apo-Sys, FP7–200767. Belgian grants: Interuniversity attraction poles, IAP 6/18. Flemish grants: Fonds Wetenschappelijke Onderzoek Vlaanderen, 3G.0218.06, 1.5.169.08N and G.0226.09; Ghent University grants: BOF-GOA – 12.0505.02. S.L. holds a grant of the Fonds voor Wetenschappelijk Onderzoek. E.H. had a grant of the Instituut voor de Aanmoediging van Innovatie door Wetenschap en Technologie’ in Vlaanderen.

332

SASKIA LIPPENS, ESTHER HOSTE, PETER VANDENABEELE, AND WIM DECLERCQ

SUGGESTED READINGS

Assefa, Z., Van Laethem, A., Garmyn, M., and Agostinis, P. (2005). Ultraviolet radiation-induced apoptosis in keratinocytes: on the role of cytosolic factors. Biochim Biophys Acta 1755, 90–106.

Candi, E., Schmidt, R., and Melino, G. (2005). The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol 6, 328–40.

Contassot, E., Gaide, O., and French, L.E. (2007). Death receptors and apoptosis. Dermatol Clin 25, 487–501, vii.

Cui, C.Y., and Schlessinger, D. (2006). EDA signaling and skin appendage development. Cell Cycle (Georgetown, Tex) 5, 2477–83.

Denecker, G., Ovaere, P., Vandenabeele, P., and Declercq, W. (2008). Caspase-14 reveals its secrets. J Cell Biol 180, 451–8.

DiDonato, J.A. (2001). IKK alpha on center stage. Sci STKE 2001, PE1.

Eferl, R., and Wagner, E.F. (2003). AP-1: a double-edged sword in tumorigenesis. Nat Rev 3, 859–868.

Kruyt, F.A. (2008). TRAIL and cancer therapy. Cancer Lett 263, 14–25.

Lippens, S., Denecker, G., Ovaere, P., Vandenabeele, P., and Declercq, W. (2005). Death penalty for keratinocytes: apoptosis versus cornification. Cell Death Differ 12 Suppl 2, 1497– 508.

Nickoloff, B.J., Qin, J.Z., Chaturvedi, V., Bacon, P., Panella, J., and Denning, M.F. (2002). Life and death signaling pathways contributing to skin cancer. J Investig Dermatol Symp Proc 7, 27– 35.

Raj, D., Brash, D.E., and Grossman, D. (2006). Keratinocyte apoptosis in epidermal development and disease. J Invest Dermatol 126, 243–57.

Ridky, T.W., and Khavari, P.A. (2004). Pathways sufficient to induce epidermal carcinogenesis. Cell Cycle (Georgetown, Tex) 3, 621–624.

Stiewe, T. (2007). The p53 family in differentiation and tumorigenesis. Nat Rev 7, 165–8.

Sur, I., Ulvmar, M., and Toftgard, R. (2008). The two-faced NFkappaB in the skin. Int Rev Immunol 27, 205–23.

Zenz, R., and Wagner, E.F. (2006). Jun signalling in the epidermis: From developmental defects to psoriasis and skin tumors. Int J Biochem Cell Biol 38, 1043–9.

Соседние файлы в предмете [НЕСОРТИРОВАННОЕ]