TWEAK/Fn14信号在皮肤急性创伤愈合中的作用

皮肤创伤愈合由炎症、增生和重塑等几个连续且相互重叠的阶段组成,涉及多种细胞类型、细胞因子与细胞外基质间复杂的相互作用。肿瘤坏死因子样细胞凋亡弱诱导剂(tumor necrosis factor-like weak inducer of apoptosis,TWEAK)通过与其受体成纤维细胞生长诱导因子14(fibroblast growth factor-inducible 14,Fn14)结合促进炎症反应、调控细胞增殖、迁移、分化和血管形成,从而在皮肤创伤愈合中发挥作用。本文旨在回顾皮肤创伤愈合和TWEAK/Fn14信号通路方面的研究进展,探索TWEAK/Fn14信号在急性皮肤创伤愈合中的重要作用。     

TWEAK/Fn14在结节性红斑患者皮损组织中的表达

目的 探讨TWEAK/Fn14信号通路在结节性红斑中的表达情况及意义。方法 收集西安交通大学第二附属医院皮肤科2021年6月-2021年10月结节性红斑患者15例,取同期正常组织为对照,行石蜡组织包埋术及病理切片,提取组织蛋白和RNA,免疫组织化学染色、实时荧光定量PCR及蛋白印迹检测TWEAK和Fn14分子在结节性红斑皮损组织和正常组织中的表达,并进行差异比较和统计学分析。结果 免疫组织化学检测结果显示,TWEAK/Fn14蛋白在正常组织中低表达,在患者皮损处显著高表达,尤其在脂肪小叶及血管周围,并伴有多种炎症细胞浸润、脂肪肉芽肿和纤维化;实时荧光定量PCR及蛋白印迹检测显示患者皮损组织中的TWEAK/Fn14信号表达显著高于正常组织对照组(P<0.05)。结论 TWEAK/Fn14信号通路可能在结节性红斑发病机制中发挥重要作用,有望成为治疗结节性红斑的潜在靶点。     

TWEAK/Fn14信号在银屑病发病机制中的作用及潜在诊疗策略

银屑病是一种常见的慢性炎症性皮肤病,以角质形成细胞异常增殖与分化为重要特征,并涉及多种炎症因子介导的免疫反应机制.肿瘤坏死因子样细胞凋亡弱诱导剂(tumor necrosis factor-like weak inducer of apoptosis,TWEAK)通过与其受体成纤维细胞生长诱导因子14(fibrobla...     

肿瘤坏死因子相关凋亡诱导配体在皮肤病的进展

肿瘤坏死因子相关凋亡诱导配体是肿瘤坏死因子超家族成员之一,具有选择性的诱导变异细胞的凋亡,对维持机体内环境的稳定具有重要作用,由于肿瘤坏死因子相关凋亡诱导配体具有调节皮肤的增生、凋亡、炎症、免疫、维持皮肤器官内环境的稳定等特点,在皮肤疾病研究中成为热点.肿瘤坏死因子相关凋亡诱导配体在黑素瘤、特应性皮炎、皮肤利什曼原虫病、银屑病关节炎等皮肤病中的研究结果,提示肿瘤坏死因子相关凋亡诱导配体可能作为某些皮肤病药物治疗的新靶点.     

芳香烃受体与皮肤病

芳香烃受体是一种配体激活转录因子,具有诱导多种重要的外源性细胞色素P450酶作用。芳香烃受体不但介导外来化学物质的毒性反应,还参与一些重要的体内生物学过程,如信号传导、细胞分化和细胞凋亡等。近年来发现,芳香烃受体表达于包括皮肤在内的多种组织和细胞,介导各种皮肤疾病的发生,如皮肤肿瘤、变态反应性皮肤病、痤疮及自身免疫性疾病等。     

白塞综合征肿瘤坏死因子相关弱凋亡诱导因子及其受体成纤维细胞生长诱导因子14表达的初步研究

<正>白塞综合征(BS)是一种慢性、可累及多系统的血管炎性疾病。临床上以口腔溃疡、生殖器溃疡、葡萄膜炎和皮肤损害等反复发作为主要特征,亦可累及胃肠道、关节、心血管、肾脏及神经等多个系统。本病可能与遗传、自身免疫、感染等多种因素有关,其具体发病机制仍不十分清楚。已有研究表明肿瘤坏死因子相关弱凋亡诱导因子(TWEAK)和成纤维细胞生长诱导因子(Fn)14与心脏、脑、肝脏、肾脏、肺部、骨骼肌及关节     

芳香烃受体在炎症性皮肤病中的研究进展

芳香烃受体是一种配体激活转录因子,具有诱导多种重要的外源性细胞色素P450酶作用。近年来研究发现,芳香烃受体不仅可介导化学物质的毒性反应,它还广泛存在于人体的各种皮肤组织细胞,例如角质形成细胞及皮脂腺细胞,该受体可参与许多重要的生物学过程,如细胞增殖和分化、免疫调节和炎症反应的发生。近期有研究表明,芳香烃受体的活化对炎症性皮肤病有益,例如特应性皮炎和银屑病等。因此,芳香烃受体可能成为潜在的皮肤病治疗靶点。     

CD30与皮肤淋巴组织增生性疾病

CD30又称Ki-1抗原,为一种分子量为120k Da的跨膜细胞因子受体,属于肿瘤坏死因子受体家族,可以参与细胞活化和分化、信号转导及免疫激活等,其表达显示了细胞的活化状态。可表达CD30的原发于皮肤淋巴组织增生性疾病主要有淋巴瘤样丘疹病、原发性皮肤间变性大细胞淋巴瘤,少见的病例还有皮肤霍奇金淋巴瘤和蕈样肉芽肿大细胞转化。本文针对上述疾病做一综述,以利于对这类皮肤病变更好诊断、鉴别诊断及治疗。     

炎症因子及信号通路在瘢痕疙瘩中的研究进展

瘢痕疙瘩是皮肤创伤后修复过程的异常产物。目前瘢痕疙瘩发病机制尚存争议,许多研究表明炎症反应在瘢痕疙瘩形成过程中发挥着关键作用。组织细胞分泌的炎症因子参与介导瘢痕疙瘩中的炎症反应,其中IL-6、TGF-β、TNF-α等作为主要的炎症因子受到研究人员的广泛关注,而且取得一定的研究进展。炎症因子激活或者抑制相应的信号通路(JAK/STAT信号通路、NF-κB信号通路和MAPK信号通路),从而调节细胞增殖、分化和凋亡以及诱导炎症反应。对各种炎症因子及相关信号通路的研究将为瘢痕疙瘩的诊断和治疗提供新的思路。     

与紫外线致皮肤损伤相关的部分信号通路研究进展

紫外线照射可使皮肤损伤,导致皮肤光老化或皮肤肿瘤.多个信号通路如Nrf2-Keap1-ARE、核因子κB、丝裂原活化蛋白激酶(MAPK)、磷脂酰肌醇-3激酶-丝氨酸/苏氨酸激酶-西罗莫司靶蛋白(PI3K-AKt-mTOR)信号通路等参与皮肤光老化和(或)皮肤肿瘤的发病.Nrf2信号通路在氧化应激状态下开启,有维持氧化还原平衡和参与细胞新陈代谢等作用.核因子κB信号通路的激活引起基质金属蛋白酶等水平上调,与皮肤老化和非黑素性皮肤癌有关.MAPK信号通路参与皮肤老化和皮肤肿瘤的进展.PI3K-AKt-mTOR信号通路主要与皮肤肿瘤相关.紫外线照射可诱导上述通路的活化,参与皮肤光老化或皮肤肿瘤的发生发展.对上述通路的进一步研究有望为抵御皮肤的光老化和皮肤肿瘤提供新的方法.     

Tumor necrosis factor‐like weak inducer of apoptosis and its receptor fibroblast growth factor‐inducible 14 are expressed in urticarial vasculitis

Tumor necrosis factor (TNF)‐like weak inducer of apoptosis (TWEAK), a member of the TNF family, has been implicated as a pro‐inflammatory cytokine in many types of autoimmune and infectious diseases. However, information about TWEAK in dermatological diseases is limited. To date, no studies have investigated the roles of TWEAK in patients with urticarial vasculitis (UV). This study aimed to assess serum TWEAK levels, together with TWEAK and fibroblast growth factor‐inducible 14 (Fn14) expressions of skin lesions in patients with UV. Serum TWEAK levels in patients with UV, together with patients with cutaneous leukocytoclastic angiitis (CLA) and healthy controls were detected by enzyme‐linked immunosorbent assay; TWEAK and Fn14 expressions of skin lesions were analyzed by immunohistochemistry. Results showed that TWEAK and Fn14 were abundantly expressed in the dermal vessel wall of lesional skin in patients with UV but not healthy controls. Serum TWEAK levels in the acute stage in patients with UV were significantly higher than those in the convalescent stage and healthy controls. Serum TWEAK levels were elevated significantly in patients with CLA compared with those in healthy controls. Our previous study indicated that TWEAK may be an important mediator for the development of vascular inflammation in skin. In addition, we also found that TWEAK blockade substantially reduced vascular damage and perivascular leukocyte infiltrates in lipopolysaccharide‐induced cutaneous vasculitis. Our study shows that TWEAK may be associated with the pathogenesis of UV; it is therefore suggested that TWEAK may be a potential therapeutic target for UV and other types of cutaneous vasculitis.     

TWEAK/Fn14 activation induces keratinocyte proliferation under psoriatic inflammation

Tumor necrosis factor (TNF)‐like weak inducer of apoptosis (TWEAK) has been reported to induce keratinocyte apoptosis in vitro by engaging its sole receptor of fibroblast growth factor‐inducible 14 (Fn14). In this study, we explored the role of TWEAK/Fn14 pathway in the growth of psoriatic keratinocytes that is, however, characterized by suppressed apoptotic cell death. Skin tissues from the patients with psoriasis or healthy donors were determined for TWEAK and Fn14 expression, and primary keratinocytes were evaluated under the stimulation of psoriatic proinflammatory cytokines or plus TWEAK. The results showed that both TWEAK and Fn14 were highly expressed in psoriatic skins. Moreover, the stimulation of psoriatic cytokines enhanced Fn14 expression by keratinocytes in vitro, which expressed TNF receptor 2 predominantly and proliferated increasingly with the addition of TWEAK. Furthermore, TWEAK stimulation enhanced the synthesis of survivin, inhibitor of apoptosis protein 2 and cellular FLICE‐inhibitory protein in lesional keratinocytes. Therefore, TWEAK/Fn14 interaction prefers to enhance proliferation but not apoptosis of keratinocytes under psoriatic inflammation. The activation of nuclear factor‐κB signalling‐dependent anti‐apoptotic proteins and biased expression of TNF receptors may be responsible for such a novel principle in keratinocytes under psoriatic inflammation.     

Induction of RANTES by TWEAK/Fn14 interaction in human keratinocytes

TNF-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor (TNF) family, is a multifunctional cytokine that regulate cellular proliferation, angiogenesis, inflammation, and apoptosis. In this study, we investigated the effect of TWEAK on human keratinocytes. Primary cultured normal human keratinocytes constitutively expressed a TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14), and produced regulated on activation, normal T expressed and secreted (RANTES) upon TWEAK stimulation in a concentration-dependent manner. The TWEAK-induced RANTES production was abrogated by anti-Fn14 antibody, and synergistically augmented by simultaneous stimulation with transforming growth factor-beta. In addition, human keratinocytes differentiated in vitro with high Ca(2+)-containing medium showed enhanced production of RANTES upon TWEAK stimulation. Furthermore, TWEAK induced rapid phosphorylation of IkappaB-alpha in human keratinocytes. Collectively, TWEAK acts on human keratinocytes as an inducer of RANTES via Fn14. Because RANTES has been implicated in inflammation, TWEAK/Fn14 interaction in human keratinocytes may be involved in the pathophysiology of inflammatory skin disorders.     

Expression of TWEAK in normal human skin, dermatitis and epidermal neoplasms: association with proliferation and differentiation of keratinocytes

Background: Tumor necrosis factor‐like weak inducer of apoptosis (TWEAK) has been implicated in the pathogenesis of various inflammatory pathologies and cancer. We aimed to investigate its expression in normal human skin, inflammatory skin diseases and epidermal neoplasms. Methods: Immunohistochemistry for TWEAK was performed in samples of healthy skin, plaque psoriasis, lichen planus, prurigo nodularis, discoid lupus erythematosus, lichen sclerosus, seborrheic keratosis, common warts, actinic keratosis, Bowen's disease, keratoacanthoma and basal and squamous cell carcinoma. Double immunofluorescence was used to investigate co‐localization of TWEAK with cytokeratin‐10 and proliferating cell nuclear antigen (PCNA). Results: TWEAK was robustly expressed in the epidermis of healthy skin and decreased in inflammatory conditions, both in the context of epidermal hyperplasia and atrophy. Decreased TWEAK immunoreactivity was regularly observed in common warts, actinic keratosis and Bowen's disease, particularly in areas of marked proliferation as evidenced by PCNA‐positive nuclei. In squamous cell carcinoma, expression of TWEAK ranged from strong to completely absent, and it mostly corresponded with the expression of cytokeratin‐10. TWEAK was absent in keratoacanthoma and basal cell carcinoma. Conclusions: TWEAK is a constitutively expressed epidermal protein whose downregulation might be an early indicator of disturbed differentiation or pathologic proliferation of keratinocytes that accompany inflammatory and neoplastic skin diseases. Peternel S, Manestar‐Bla?i? T, Brajac I, Prpi?‐Massari L, Ka?telan M. Expression of TWEAK in normal human skin, dermatitis and epidermal neoplasms: association with proliferation and differentiation of keratinocytes.     

Influence of narrowband ultraviolet B phototherapy on serum tumour necrosis factor‐like weak inducer of apoptosis (TWEAK) in patients with psoriasis

Psoriasis is characterized by keratinocyte resistance to apoptosis. We recently demonstrated an increase in serum tumour necrosis factor‐like weak inducer of apoptosis (TWEAK) in patients after topical treatment for psoriasis. We decided to verify whether narrowband ultraviolet B (NB‐UVB) has a similar effect. Serum concentration of TWEAK was estimated in patients with exacerbated plaque psoriasis treated with NB‐UVB. Baseline TWEAK levels were similar in patients with psoriasis and healthy controls, and Psoriasis Area and Severity Index (PASI) correlated inversely with TWEAK levels. Treatment with NB‐UVB caused a significant reduction in PASI and concurrent increase in serum TWEAK. This finding may be due to increased expression of TWEAK receptor in psoriatic skin, which has been reported previously, with consequent binding of excess soluble TWEAK during treatment and subsequent release after treatment. Severity of plaque psoriasis and its improvement after NB‐UVB treatment may be associated with TWEAK concentrations. The importance of our findings remains to be established.     

Stat 3与相关皮肤病

Stat3是一种重要的核转录因子,参与细胞增殖、存活、转化、迁移等过程。Stat3在以表皮过度增殖和/或异常分化为特征的皮肤病,如银屑病、皮肤恶性肿瘤的发病中起重要作用。通过向目的细胞内引入Stat3反义寡核苷酸、诱饵寡核苷酸或显性负相蛋白等阻断Stat3的功能,能抑制目的细胞的增殖,促进细胞调亡。     

肿瘤坏死因子拮抗剂在治疗非银屑病性皮肤病中的临床应用

肿瘤坏死因子拮抗剂通过阻断肿瘤坏死因子与其受体的结合而阻止胞内信号的传递、下游炎症因子的激活及细胞增殖而达到抗炎作用。用于临床的肿瘤坏死因子拮抗剂主要包括英夫利昔单抗（IFX）、依那西普( ENT)、阿达木单抗( ADA)等,在皮肤科中已广泛应用于非银屑病的治疗,本文对其进行了综述。