Galectin-3 protects keratinocytes from UVB-induced apoptosis by enhancing AKT activation and suppressing ERK activation

Keratinocytes undergo apoptosis in a variety of physiological and pathological conditions. Galectin-3 is a member of a family of beta-galactoside-binding animal lectins expressed abundantly in keratinocytes and other epithelial cells. Here, we have studied the regulatory role of galectin-3 in keratinocyte apoptosis by using cells from gene-targeted galectin-3 null (gal3(-/-)) mice. We showed that galectin-3 mRNA was transiently upregulated in ultraviolet-B (UVB)-irradiated wild-type keratinocytes. We found that gal3(-/-) keratinocytes were significantly more sensitive to apoptosis induced by UVB as well as various other stimuli, both in vitro and in vivo, than wild-type cells. Moreover, we demonstrated that increased apoptosis in gal3(-/-) keratinocytes was attributable to higher extracellular signal-regulated kinase (ERK) activation and lower AKT activation after UVB irradiation. We conclude that endogenous galectin-3 is an anti-apoptotic molecule in keratinocytes functioning by suppressing ERK activation and enhancing AKT activation and may play a role in the development of apoptosis-related skin diseases.     

半乳糖凝集素与皮肤病研究进展

半乳糖凝集素家族是一类内源性凝集素家族,与含β-半乳糖苷残基的多聚糖具有高亲和力,目前已有15个半乳糖凝集素家族成员被发现,其广泛分布于上皮细胞和免疫细胞,参与细胞的生长分化、细胞间的粘附、细胞信号转导及细胞凋亡等多种细胞活动。其中,半乳糖凝集素-1,-3,-7,-9,-12参与皮肤肿瘤、创面愈合、银屑病、硬皮病、系统性红斑狼疮、特应性皮炎、白癜风等多种皮肤病的疾病进程,有望作为疾病发展和预后的生物标记物。本文对近年来半乳糖凝集素-1,-3,-7,-9,-12及相关皮肤病研究进展进行综述。     

Galectins and cutaneous immunity

Galectins are highly expressed in epithelial cells and immune cells. In skin, they can be detected in keratinocytes, melanocytes, dendritic cells, macrophages, and T cells. Galectins are present outside and inside the cells and thus may exhibit different functions through extracellular and intracellular actions. Galectins can be involved in the pathogenesis of inflammatory skin diseases by affecting growth, apoptosis, maturation, activation, and motility of keratinocytes and immune cells. Expression of galectins may change depending on the cellular status, such as proliferation and activation. For example, galectin-3 expression is upregulated in T cells but downregulated in dendritic cells when these cells are activated. Furthermore, their expression may also change under pathological conditions. Understanding the function of each galectin in keratinocytes and different immune cell types may reveal how galectins contribute to the pathogenesis of immune-mediated skin diseases.     

骨桥蛋白与皮肤疾病

骨桥蛋白是一种表达于多种组织和细胞的糖蛋白,通过翻译后修饰而在细胞内外存在多种活性形式,可结合不同的受体发生信号转导,介导细胞黏附和迁移、肿瘤侵袭及抗凋亡作用,参与包括Th17在内的Th细胞系的调节.骨桥蛋白能加强机体对分枝杆菌和病毒抗感染能力,且在自身免疫病、银屑病中大量表达,能影响速发性和迟发性变态反应引起的炎症和肉芽肿形成.对骨桥蛋白进行深入研究将为人们治疗相关皮肤病带来新的手段.     

骨桥蛋白与皮肤疾病

骨桥蛋白是一种表达于多种组织和细胞的糖蛋白,通过翻译后修饰而在细胞内外存在多种活性形式,可结合不同的受体发生信号转导,介导细胞黏附和迁移、肿瘤侵袭及抗凋亡作用,参与包括Th17在内的Th细胞系的调节.骨桥蛋白能加强机体对分枝杆菌和病毒抗感染能力,且在自身免疫病、银屑病中大量表达,能影响速发性和迟发性变态反应引起的炎症和肉芽肿形成.对骨桥蛋白进行深入研究将为人们治疗相关皮肤病带来新的手段.     

EGFR通路在相关皮肤病发病机制中的研究进展

表皮生长因子受体（EGFR）是一种受体酪氨酸激酶，存在于几乎所有上皮细胞和多种间充质细胞的细胞膜上，EGFR通路的失调可能导致细胞增殖、血管生成、细胞凋亡受损、细胞侵袭性增强，影响银屑病、特应性皮炎等炎症性皮肤病和皮肤鳞状细胞癌、黑素瘤等肿瘤性皮肤病的发生与发展，本文综述了EGFR通路在相关皮肤病发病机制中的研究进展。     

骨桥蛋白与皮肤疾病

骨桥蛋白是一种表达于多种组织和细胞的糖蛋白,通过翻译后修饰而在细胞内外存在多种活性形式,可结合不同的受体发生信号转导,介导细胞黏附和迁移、肿瘤侵袭及抗凋亡作用,参与包括Th17在内的Th细胞系的调节.骨桥蛋白能加强机体对分枝杆菌和病毒抗感染能力,且在自身免疫病、银屑病中大量表达,能影响速发性和迟发性变态反应引起的炎症和肉芽肿形成.对骨桥蛋白进行深入研究将为人们治疗相关皮肤病带来新的手段.     

骨桥蛋白与皮肤疾病

骨桥蛋白是一种表达于多种组织和细胞的糖蛋白,通过翻译后修饰而在细胞内外存在多种活性形式,可结合不同的受体发生信号转导,介导细胞黏附和迁移、肿瘤侵袭及抗凋亡作用,参与包括Th17在内的Th细胞系的调节.骨桥蛋白能加强机体对分枝杆菌和病毒抗感染能力,且在自身免疫病、银屑病中大量表达,能影响速发性和迟发性变态反应引起的炎症和肉芽肿形成.对骨桥蛋白进行深入研究将为人们治疗相关皮肤病带来新的手段.     

角质形成细胞的凋亡失调及相关皮肤病

角质形成细胞的凋亡在调节表皮发育和抑癌中起着关键作用，凋亡可平衡角质形成细胞的增殖来保持表皮厚度，促使角质层形成和清除恶化前细胞。除正常发展程序外，角质形成细胞的凋亡能被紫外线和其他刺激诱发，凋亡在保持皮肤细胞内环境稳定和一些皮肤病的发病机制中起着重要作用。     

皮肤病中c-Jun氨基末端蛋白激酶通路的研究现况

c-Jun氨基末端蛋白激酶是丝裂原活化蛋白激酶家族的成员,调节细胞的生长、发育、增殖和分化.c-Jun氨基末端蛋白激酶的异常表达与人皮肤疾病的发生、发展密切相关.研究证实,c-Jun氨基末端蛋白激酶在多种皮肤疾病患者的真/表皮中表达过度增高及异常活化,进而导致细胞的生长、发育、增殖、分化异常以及炎症反应和细胞凋亡的发生.选择阻断c-Jun氨基末端蛋白激酶通路的异常活化可以使病情得到改善.针对c-Jun氨基末端蛋白激酶信号通路的靶向治疗已经成为目前多种皮肤病的研究热点.     

PPARdelta is a type 1 IFN target gene and inhibits apoptosis in T cells

Peroxisome proliferator-activated receptor beta/delta (PPARdelta) is a nuclear hormone receptor regulating diverse biological processes, including beta-oxidation of fatty acid and epithelial cell differentiation. To date, the role of PPARdelta in the immune system has not been thoroughly studied. Here, we show that PPARdelta is expressed in activated human T cells purified from peripheral blood as well as in T cells isolated from affected psoriasis skin lesions. PPARdelta is induced in T cells on stimulation with type 1 IFN. Functionally, PPARdelta enhances proliferation of primary T cells and blocks apoptosis induced by type 1 IFN and by serum deprivation. We show that these cellular functions are mediated by the activation of extracellular signal-regulated kinase1/2 signaling. Our results (1) establish a direct molecular link between type 1 IFN signaling and PPARdelta, (2) define a functional role for PPARdelta in human T cells, and (3) suggest that the induction of PPARdelta by type 1 IFN contributes to the persistence of activated T cells in psoriasis skin lesions.     

Osteopontin and the skin: multiple emerging roles in cutaneous biology and pathology

Abstract:  Osteopontin (OPN) is a glycoprotein expressed by various tissues and cells. The existence of variant forms of OPN as a secreted (sOPN) and intracellular (iOPN) protein and its modification through post-translational modification and proteolytic cleavage explain its broad range of functions. There is increasing knowledge which receptors OPN isoforms can bind to and which signaling pathways are activated to mediate different OPN functions. sOPN interacts with integrins and CD44, mediates cell adhesion, migration and tumor invasion, and has T helper 1 (Th1) cytokine functions and anti-apoptotic effects. iOPN has been described to regulate macrophage migration and interferon-α secretion in plasmacytoid dendritic cells. Both sOPN and iOPN, through complex functions for different dendritic cell subsets, participate in the regulation of Th cell lineages, among them Th17 cells. For skin disease, OPN from immune cells and tumor cells is of pathophysiological relevance. OPN is secreted in autoimmune diseases such as lupus erythematosus, and influences inflammation of immediate and delayed type allergies and granuloma formation. We describe that OPN is overexpressed in psoriasis and propose a model to study OPN function in psoriatic inflammation. Through cytokine functions, OPN supports immune responses against Mycobacteria and viruses such as herpes simplex virus. OPN is also implicated in skin tumor progression. Overexpression of OPN influences invasion and metastasis of melanoma and squamous cell carcinoma cells, and OPN expression in melanoma is a possible prognostic marker. As OPN protein preparations and anti-OPN antibodies may be available in the near future, in-depth knowledge of OPN functions may open new therapeutic approaches for skin diseases.     

Distribution of apoptosis-mediating Fas antigen in human skin and effects of anti-Fas monoclonal antibody on human epidermal keratinocyte and squamous cell carcinoma cell lines

Fast antigen is a cell surface protein that mediates apoptosis. Using immunohistological, flow cytometry and electron microscopic analyses, we investigated the expression of Fas antigen on various skin tissues, and on cultured SV40-transformed human epidermal keratinocyte cell line KJD and human skin squamous cell carcinoma cell line HSC. The Fas antigen was widely distributed in skin components such as the keratinocytes in the lower portion of the epidermis, epidermal dendritic cells, endothelial cells, fibroblasts, apocrine glands, eccrine sweat glands, sebaceous glands, some normal melanocytes and infiltrating lymphoid cells. It was also strongly expressed on the keratinocytes of lichenoid eruptions seen in lupus erythematosus and lichen planus, and on the spongiotic or acanthotic epidermis seen in chronic eczema, adult T-cell leukaemia/lymphoma (ATLL) and atopic dermatitis. Its expression was closely correlated with lymphoid infiltrating cells and it was strongly expressed in lymphoid neoplastic cells, particularly ATLL cells, and fibroblasts seen in dermatofibroma. However, the antigen was not detected on basal cell epithelioma cells, some malignant melanomas or any junctional naevi. The cell lines KJD and HSC strongly expressed the Fas antigen, and crosslinking of the Fas antigen by an anti-Fas monoclonal antibody induced apoptosis of these cell lines. These results indicate that the apoptosis-mediating Fas antigen may play an important role in normal skin turnover and cell differentiation, in immune regulation of skin tumours, and in the pathogenesis of various skin diseases.     

UV-induced squamous cell carcinoma – a role for antiapoptotic signalling pathways

The incidence of nonmelanoma skin cancer including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) has dramatically increased in the last decades, and chronic sun exposure was identified as a main etiologic agent. UV radiation may produce DNA damage either directly or through reactive oxygen species (ROS). As mutations caused by UV may lead to skin cancer due to oncogene activation and tumor suppressor gene inactivation, efficient safeguard mechanisms have been developed during evolution. These enclose induction of apoptosis and formation sunburn cells aiming at the removal of premalignant cells. The keratinocyte apoptotic machinery in response to UV consists of both intrinsic/mitochondrial and extrinsic/death receptor-mediated cell-death pathways, which are particularly regulated by mitogen-activated protein kinases (MAPKs, JNK and p38) and the tumor-suppressor protein p53. For development of skin cancer, it appears that critical steps in apoptosis control are dysregulated leading to resistance both to death ligand-mediated and intrinsic proapoptotic pathways. These particularly include inactivation of p53, as well as activation of EGFR, COX-2 and MAPKs, which result in specific regulation of Bcl-2 proteins, death ligands and death receptors. The final unravelling of apoptosis regulation in epithelial skin cancer may allow the development of new targeted therapeutic strategies.     

Peroxisome Proliferator-Activated Receptors (PPARs) and the Human Skin

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily that regulate lipid, glucose, and amino acid metabolism. More recently, PPARs and corresponding ligands have been shown in skin and other organs to regulate important cellular functions, including cell proliferation and differentiation, as well as inflammatory responses. These new functions identify PPARs and corresponding ligands as potential targets for the treatment of various skin diseases and other disorders. It has been shown that in inflammatory skin disorders, including hyperproliferative psoriatic epidermis and the skin of patients with atopic dermatitis, the expression of both PPARalpha and PPARgamma is decreased. This observation suggests the possibility that PPARalpha and PPARgamma activators, or compounds that positively regulate PPAR gene expression, may represent novel NSAIDs for the topical or systemic treatment of common inflammatory skin diseases such as atopic dermatitis, psoriasis, and allergic contact dermatitis. Moreover, recent findings indicate that PPAR-signaling pathways may act as a promising therapeutic target for the treatment of hyperproliferative skin diseases including skin malignancies. Studies in non-diabetic patients suggest that oral thiazolidinediones, which are synthetic ligands of PPARgamma, not only exert an antidiabetic effect but also may be beneficial for moderate chronic plaque psoriasis by suppressing proliferation and inducing differentiation of keratinocytes; furthermore, they may even induce cell growth arrest, apoptosis, and terminal differentiation in various human malignant tumors. It has been reported that PPARalpha immunoreactivity is reduced in human keratinocytes of squamous cell carcinoma (SCC) and actinic keratosis (AK), while PPARdelta appears to be upregulated. Additionally, the microvessel density is significantly higher in AK and SCC that express high levels of PPARdelta. PPARdelta has been demonstrated to have an anti-apoptotic role and to maintain survival and differentiation of epithelial cells, whereas PPARalpha and PPARgamma activators induce differentiation and inhibit proliferation and regulate apoptosis. In melanoma, the growth inhibitory effect of PPARgamma activation is independent of apoptosis and seems to occur primarily through induction of cell cycle arrest in the G1 phase of the cell cycle or induction of re-differentiation. PPARalpha activation causes inhibition of migration of melanoma cells and anchorage-independent growth, whereas primary tumor growth remains unaltered. In clinical trials of gemfibrozil, a PPARalpha ligand, significantly fewer patients treated with this lipid-lowering drug were diagnosed with melanoma as compared to those in the control group. In conclusion, an increasing body of evidence indicates that PPAR signaling pathways may represent interesting therapeutic targets for a broad variety of skin disorders, including inflammatory skin diseases such as psoriasis and atopic dermatitis, and skin malignancies.     

Recombinant gamma interferon induces HLA-DR expression on squamous cell carcinoma,trichilemmoma, adenocarcinoma cell lines,and cultured human keratinocytes

Summary We investigated the effects of recombinant human gamma interferon on the induction of HLA-DR expression by two human squamous cell carcinoma, three trichilemmoma, one eccrine carcinoma, two adenocarcinoma cell lines, and cultured human keratinocytes in vitro. None of eight epithelial cell lines or keratinocytes expressed HLA-DR without gamma interferon treatment. In contrast, pure gamma interferon (500 IU/ml, 72-h treatment) induced HLA-DR expression on 1/2 squamous cell carcinoma, 3/3 trichilemmoma, 2/2 adenocarcinoma cell lines, and 4/4 kerationcyte cell lines, as determined using a fluorescence-activated cell sorter. A maxillary squamous cell carcinoma line and an eccrine carcinoma cell line failed to express HLA-DR with gamma interferon treatment; however, the growth of cells was inhibited by gamma interferon treatment. By indirect immunoperoxidase techniques, tumor cells such as Bowen's disease and squamous cell carcinoma were found to express HLA-DR. Since HLA-DR expression has been shown to be important for various immune responses, these findings suggest that gamma interferon plays important roles in various immune-related skin diseases.     

Notch信号通路在皮肤病的研究进展

Notch信号通路是一条进化上十分保守的信号转导系统.Notch受体与相邻细胞的配体相互作用转导细胞信号,从而影响细胞的增殖、分化和凋亡.较多文献表明,Notch信号通路在维持皮肤正常生理功能以及炎症性皮肤病、自身免疫性皮肤病、皮肤肿瘤、色素性皮肤病等多种皮肤病中发挥重要作用.尽管目前临床应用尚不成熟,Notch信号抑制剂和激活剂有希望为皮肤病的治疗提供新思路.     

七种细胞角蛋白在皮肤上皮性肿瘤中的表达

目的 观察7种细胞角蛋白在皮肤上皮性肿瘤中的表达,并探讨其意义.方法 应用免疫组化S-P法对54例不同的皮肤上皮性肿瘤和20例正常皮肤进行细胞角蛋白7(K72.2)、细胞角蛋白8(C-51)、细胞角蛋白10(DE-K10)、细胞角蛋白14(LL002)、细胞角蛋白17(E3)、细胞角蛋白18(DC10)、细胞角蛋白19(KS19.1)标记,观察不同细胞角蛋白的表达.结果 54例皮肤上皮性肿瘤包括,鳞状细胞癌10例、基底细胞癌10例、毛发肿瘤19例、皮脂腺癌2例、汗腺肿瘤13例.皮肤上皮性肿瘤中7种细胞角蛋白的表达和分布有所不同.鳞状细胞癌、基底细胞癌和毛发分化的肿瘤中细胞角蛋白多数呈弥漫表达;而汗腺分化的肿瘤中,不同部位表达不同细胞角蛋白,每种肿瘤各有特点.结论 选择地检测一组细胞角蛋白的联合表达,有助于皮肤上皮性肿瘤的诊断和鉴别诊断.     

Metabolic inhibition of galectin-1-binding carbohydrates accentuates antitumor immunity

Galectin-1 (Gal-1) has been shown to play a major role in tumor immune escape by inducing apoptosis of effector leukocytes and correlating with tumor aggressiveness and disease progression. Thus, targeting the Gal-1/Gal-1 ligand axis represents a promising cancer therapeutic approach. Here, to test the Gal-1-mediated tumor immune evasion hypothesis and demonstrate the importance of Gal-1-binding N-acetyllactosamines in controlling the fate and function of antitumor immune cells, we treated melanoma- or lymphoma-bearing mice with peracetylated 4-fluoro-glucosamine (4-F-GlcNAc), a metabolic inhibitor of N-acetyllactosamine biosynthesis, and analyzed tumor growth and immune profiles. We found that 4-F-GlcNAc spared Gal-1-mediated apoptosis of T cells and natural killer (NK) cells by decreasing their expression of Gal-1-binding determinants. 4-F-GlcNAc enhanced tumor lymphocytic infiltration and promoted elevations in tumor-specific cytotoxic T cells and IFN-γ levels, while lowering IL-10 production. Collectively, our data suggest that metabolic lowering of Gal-1-binding N-acetyllactosamines may attenuate tumor growth by boosting antitumor immune cell levels, representing a promising approach for cancer immunotherapy.     

生存素与皮肤肿瘤相关性的研究进展

生存素基因是凋亡抑制蛋白家族新成员,因其结构较为独特,且能选择性地在肿瘤中表达,正常终末分化组织中不表达,是皮肤鳞癌、恶性黑素瘤的预后指标;抑制其表达能显著促进常见皮肤恶性肿瘤细胞发生凋亡,对正常组织无明显影响,有望成为肿瘤标记物和肿瘤治疗的新靶点。