Keratinocyte apoptosis in epidermal development and disease

Keratinocyte (KC) apoptosis plays a critical role in regulating epidermal development and restraining carcinogenesis. Apoptosis balances proliferation to maintain epidermal thickness, contributes to stratum corneum formation and may eliminate pre-malignant cells. Apart from the normal developmental program, KC apoptosis can be triggered by UV light and other stimuli. Dysfunctional apoptosis occurs in some skin diseases, such as psoriasis and skin cancer. Here we review the current state of knowledge of KC apoptosis, with particular focus on apoptotic signaling pathways and molecular mechanisms of apoptosis control, and discuss new insights into the complex role of apoptosis in skin carcinogenesis that are emerging from mouse models.     

Keratinocyte apoptosis induced by ultraviolet B radiation and CD95 ligation -- differential protection through epidermal growth factor receptor activation and Bcl-x(L) expression.

Previous work has shown that activation of the epidermal growth factor receptor by endogenous or exogenous signals markedly enhances survival of cultured keratinocytes upon cellular stress such as passaging. This is due, in part, to epidermal-growth-factor-receptor-dependent expression of Bcl-x(L), an antiapoptotic Bcl-2 homolog. In this study we tested whether epidermal-growth-factor-receptor-dependent signal transduction and attendant Bcl-x(L) expression affected survival of human keratinocytes upon exposure to a frequently encountered apoptotic stimulus, radiation with ultraviolet B. We describe that blocking epidermal-growth-factor-receptor-dependent signal transduction sensitized normal keratinocytes to undergo apoptosis upon ultraviolet B radiation with solar light characteristics. Forced expression of Bcl-x(L) partially but significantly inhibited ultraviolet-B-induced apoptosis of immortalized keratinocytes (HaCaT). Bcl-x(L) overexpression afforded no protection to HaCaT cells against apoptosis induced by binding of an agonist antibody to the death receptor CD95, however. CD95 activation has previously been shown to functionally contribute to apoptosis in ultraviolet-irradiated keratinocytes. These results indicate that epidermal growth factor receptor activation and attendant Bcl-x(L) expression provided a physiologically relevant protective pathway of keratinocytes against ultraviolet-induced but not CD95-dependent apoptosis.     

Aloesin inhibits hyperpigmentation induced by UV radiation

Skin hyperpigmentation is caused by the overproduction of melanin pigment, which is synthesized by the action of tyrosinase. We recently reported that aloesin inhibits tyrosinase activity. The present study was undertaken to test the inhibitory effect of aloesin on pigmentation in human skin after UV radiation. Experimental subjects were UV-irradiated (210 mJ) on the inner forearm. UV-irradiated regions were assigned to four groups: vehicle control, aloesin treated, arbutin treated, and aloesin and arbutin treated. Aloesin and/or arbutin were administered four times a day for 15 days. Aloesin treatment suppressed pigmentation by 34%, arbutin by 43.5%, and the cotreatment by 63.3% compared with the control (n = 15; P < 0.05). Moreover, aloesin treatment showed pigmentation suppression in a dose-dependent manner (n = 7; P < 0.05). These results raise the possibility that aloesin may be used as an agent that inhibits melanin formation induced by UV radiation.     

Photoadaptation to ultraviolet (UV) radiation in vivo: photoproducts in epidermal cells following UVB therapy for psoriasis

BACKGROUND: Ultraviolet (UV) radiation is mutagenic and induces specific DNA lesions in human skin that are often found at dipyrimidine sites. These photoproducts are likely to be biologically relevant regarding skin carcinogenesis, as p53 mutations in skin tumours are most often found at these UV radiation-specific sites within DNA. Psoriasis patients receiving long-term phototherapy are at an increased risk of non-melanoma skin cancers. OBJECTIVES: The aim of this study was to quantify DNA photoproducts in human epidermis in vivo following consecutive doses of UVB and to investigate variations in DNA damage according to skin type, UVB dose and age. METHODS: Eleven psoriasis patients receiving UVB phototherapy three times a week were recruited and underwent skin biopsies on a non-sun-exposed site before starting phototherapy and after three, nine and 18 UVB exposures. A biopsy was also taken at least 4 weeks after stopping phototherapy. DNA was extracted from separated epidermis and three types of photoproducts were quantified using a novel 32P high-performance liquid chromatographic technique. RESULTS: The mean level of cyclobutane dipyrimidine dimers (CPDs) after three doses of UVB (dose range 0.03-0.15 J cm-2) was 3.2 (range 0.8-8.9) photoproducts per 106 normal nucleotides for TT=T dimers and 4.5 (range 0-14) per 106 normal nucleotides for TT=C dimers. The mean levels of TT-C 6-4 photoproducts after three doses of UVB were very low (0.2, range 0-1.8). Overall, the levels of TT=T and TT=C reached a plateau at three exposures and were found to decrease for subsequent exposures despite increasing UVB doses. Skin type was negatively associated with mean levels of CPDs. However, significant differences in levels of photoproducts were seen between individuals, even after adjusting for skin type. No association was found between challenge dose of UVB and photoproduct yield in this study. CONCLUSIONS: This study showed a great individual variation in the accumulation of DNA photoproducts following exposure to repetitive doses of UVB. Photoadaptive responses of human skin involving DNA repair, tanning and epidermal thickening are likely to explain the overall lack of increase in DNA lesions throughout phototherapy. This in vivo study confirms that psoriasis patients produce a significant amount of DNA photolesions at suberythemal doses of UVB. Further work is needed to investigate which host factors are most likely to predict susceptibility to UV radiation-induced DNA damage.     

紫外线辐射对皮肤细胞骨架影响的蛋白质组学研究

目的:初步探讨紫外线辐射所致皮肤细胞骨架蛋白质组整体变化规律.方法:分别提取30 mJ/cm2中波紫外线(UVB)照射前后角质形成细胞HaCaT株和10 J/cm2长波紫外线(UVA)照射前后成纤维细胞的总蛋白,采用固相pH梯度双向凝胶电泳技术进行分离经Imaging Master 2D软件分析双向电泳图谱以发现差异表达蛋白,并对部分差异表达蛋白进行胶内酶切、基质辅助激光解吸电离飞行时间(MALDI-TOF)质谱分析,测定其肽质量指纹图谱.在网上蛋白质数据库检索鉴定差异蛋白.结果:获得良好的双向电泳图谱,图像分析显示在紫外线辐射前后很多蛋白质发生差异表达,对差异表达的部分蛋白点进行肽质量指纹图谱分析,经Mascot软件检索人非冗余蛋白质数据库后,鉴定出7个涉及皮肤细胞骨架的蛋白质:微管蛋白α2和微管蛋白β5,角蛋白1 K7、角蛋白K8、角蛋白K13、角蛋白K18和角蛋白K19.对它们的功能和与紫外线辐射的可能天系进行了初步探讨.结论:紫外线辐射可以诱导皮肤细胞骨架蛋白质组发生改变,而这些骨架蛋白的变化不仅与皮肤细胞应对紫外线辐射并清除其损伤密切相关,还可能进一步参与紫外线诱导的细胞凋亡及细胞癌变.     

Psoriatic architecture constructed by epidermal remodeling

Epidermal remodeling is the concept that epidermal architecture is determined by a simple self-organizing mechanism; epidermal hyperproliferation constructs typical psoriatic architecture. This is based on the assumption that the enlargements in both the two-dimensional proliferative compartment (basal cell layer) and three-dimensional whole epidermal volume coexist. During this process, the dermal papillae become markedly, but passively, expanded by enlargement of the proliferative compartment. This creates a considerable shrinkage force against the crowded basal cell layer, which is forced to lose adherence to the dermal extracellular matrix (ECM). This results in anoikis, a type of apoptosis characterized by cell detachment, and, consequently, a markedly diminished epidermal turnover time in psoriasis. The papillary shrinkage force also explains the fact that dermal papillary height does not exceed a certain limit. At the cessation of hyperproliferation a normalisation remodeling takes place toward normal tissue architecture. Thus the concept of epidermal remodeling explains the self-organizing mechanism of the architectural change in psoriasis, which is essentially a reversible disorder depending on epidermal hyperproliferation.     

尖锐湿疣角质形成细胞Fas表达与凋亡

目的：探讨尖锐湿疣(CA)角质形成细胞Fas表达与凋亡的关系。方法：对51例CA和18例正常上皮分别采用免疫组化ABC法检测Fas抗原、末端脱氧核苷酸转移酶介导的cUTP缺口末端标记技术检测细胞凋亡。结果：CA皮损Fas指数显著高于正常上皮(P=0．004)，CA皮损与正常上皮捌亡指数无明显差异(P=0．664)，CA皮损Fas指数与凋亡指数无明显相开关性(P=0．647)。结论：CA皮损存在Fas的过表达，CA皮损Fas的过表达并未引起细胞凋亡的相应增多。     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.     

重症大疱性药疹角质形成细胞凋亡的研究

重症多形红斑和中毒性表皮坏死松解症属于重症大疱性药疹,临床表现为广泛的表皮坏死剥脱,组织病理表现为广泛的角质形成细胞凋亡,表皮与真皮分离.研究认为,穿孔素/颗粒酶和Fas/FasL可能是参与诱导角质形成细胞凋亡的主要因素;提出可在支持疗法基础上联合应用多种抗凋亡药物.因此,文中对重症大疱性药疹的抗凋亡治疗进行综述.