Upregulation of cathepsin S in psoriatic keratinocytes

Please cite this paper as: Upregulation of cathepsin S in psoriatic keratinocytes. Experimental Dermatology 2010; 19 : e80–e88. Abstract: Cathepsin S (CATS) is a cysteine protease, well known for its role in MHC class II‐mediated antigen presentation and extracellular matrix degradation. Disturbance of the expression or metabolism of this protease is a concomitant feature of several diseases. Given this importance we studied the localization and regulation of CATS expression in normal and pathological human/mouse skin. In normal human skin CATS‐immunostaining is mainly present in the dermis and is localized in macrophages, Langerhans, T‐ and endothelial cells, but absent in keratinocytes. In all analyzed pathological skin biopsies, i.e. atopic dermatitis, actinic keratosis and psoriasis, CATS staining is strongly increased in the dermis. But only in psoriasis, CATS‐immunostaining is also detectable in keratinocytes. We show that cocultivation with T‐cells as well as treatment with cytokines can trigger expression and secretion of CATS, which is involved in MHC II processing in keratinocytes. Our data provide first evidence that CATS expression (i) is selectively induced in psoriatic keratinocytes, (ii) is triggered by T‐cells and (iii) might be involved in keratinocytic MHC class II expression, the processing of the MHC class II‐associated invariant chain and remodeling of the extracellular matrix. This paper expands our knowledge on the important role of keratinocytes in dermatological disease.     

RANTES在银屑病患者角质形成细胞中的表达及其作用

目的：探讨银屑病皮损局部T淋巴细胞高度浸润的原因，并分析了趋化因子RANTES在此过程中的作用。方法：培养银屑病患者皮损处角质形成细胞，通过微孔小室实验检测其上清液对T淋巴细胞的趋化功能；通过酶联免疫吸附(ELISA)法检测上清液中RANTES的表达。结果：银屑病皮损处角质形成细胞培养上清液对T淋巴细胞的趋化能力明显强于正常对照组；其分泌的RANTES水平也高于正常人。结论：银屑病患者皮损局部T淋巴细胞的大量浸润，部分是由于角质形成细胞具有较强的趋化T淋巴细胞能力，而银屑病角质形成细胞中高表达的RANTES可能是发挥此作用趋化因子之一。     

K16 expression in uninvolved psoriatic skin: a possible marker of pre-clinical psoriasis

BACKGROUND: K16, a type I keratin, is upregulated in hyperproliferative states including psoriasis. It has been used as a marker of psoriasis and its expression is upregulated in relapsing psoriasis and downregulating in resolving. We evaluated non-lesional psoriatic skin for K16 expression. METHODS: Sixty-seven non-lesional and lesional skin samples from patients with psoriasis and normal skin from 19 non-psoriatic patients were studied by immunohistochemistry on frozen sections with K16. RESULTS: Seventeen of 19 normal skin samples showed staining of basal cells in the deeper part of the rete ridges. Sixty-two non-lesional psoriatic skin samples showed intense basal staining of K16. Of the remaining five non-lesional samples, diffuse intense suprabasal staining in one, pan-epidermal staining in two, and no staining was seen in two samples. Suprabasal (37), diffuse (14), sandwich (12), and basal (3) pattern staining were seen in psoriatic skin. One psoriatic skin sample did not show any expression. CONCLUSION: Our results demonstrate that K16 expression is also observed in non-lesional psoriatic skin and may serve as a marker of preclinical psoriasis.     

Lithium and psoriasis: cytokine modulation of cultured lymphocytes and psoriatic keratinocytes by lithium

The predominant cutaneous side effect of lithium is the exacerbation or aggravation of psoriasis, but the pathogenesis is still unclear. The hyperproliferation of keratinocytes and a dense lesional infiltrate of mononuclear cells are the hallmarks of psoriatic skin lesions. Interactions between keratinocytes and T cells are thought to be one reason for an increased secretion of proinflammatory cytokines and growth factors. To investigate whether lithium influences cytokines of the ‘psoriatic cytokine network’, we established a coculture model with keratinocytes from psoriatic patients and from healthy controls cultured with HUT 78 lymphocytes and measured the cytokine levels of Il-2, Il-6, Il-8, IFNγ and TGFα in the culture supernatants after treatment with lithium. Il-6 levels were slightly elevated in the supernatants obtained from psoriatic and control keratinocyte cultures after lithium treatment, but IFNγ and Il-2 levels were elevated only in the lithium-treated cocultures with psoriatic keratinocytes. In contrast, these two cytokines were not affected by lithium in HUT 78 monocultures or in cocultures with normal epidermal cells. We also found slightly elevated TGFα levels in lithium-treated psoriatic cocultures but not in control cultures. We therefore demonstrated that lithium influences the cell communication of psoriatic keratinocytes with HUT 78 lymphocytes by triggering the secretion of TGFα, Il-2 and, massively, IFNγ. It seems possible that lithium also influences similar parts of the psoriatic cytokine network in vivo. Received: 19 May 1995     

Echinococcosis: a possible etiology in psoriatic disease

We aimed to investigate seroprevalence of Echinococcus granulosus in patients with psoriasis to determine a possible etiologic role, since both echinococcosis and psoriasis are defined as T cell-mediated diseases. Forty psoriatic patients and 50 age- and sex-matched control subjects were included in the study. IgG-specific ELISA was used to determine seropositivity. E. granulosus-specific IgG antibodies were found to be positive in 17/40 (42.5%) of the patients with psoriasis and in 11/50 (22%) of the control subjects (p = 0.008). Our results suggest that echinococcosis might be one of the causative pathogens in the etiopathogenesis of psoriasis in highly endemic regions.     

砷化物抑制银屑病角质形成细胞增殖的研究

银屑病主要表现为角质形成细胞过度增殖及凋亡异常,其中角质形成细胞过度增殖是由于细胞凋亡功能障碍或失调所致,凋亡缺陷在银屑病的发病机制巾发挥着重要作用。研究表明,砷化物可以通过对Fas/Fas配体、端粒和端粒酶的影响以及联合阻断JNK等多种途径诱导角质形成细胞凋亡,从而抑制其过度增殖。因此,砷化物有望成为一种局部治疗银屑病的新型药物。     

Interferon-gamma-induced 15-lipoxygenase-2 expression in normal human epidermal keratinocytes and a pathogenic link to psoriasis vulgaris

Epidermal keratinocytes contain 15-lipoxygenase, which generates 15-hydroxyeicosatetraenoic acid, a major metabolite of arachidonic acid. Although two isozymes, 15-lipoxygenase-1 and -2, exist, it remains unclear which isozyme plays an important role in inflammatory processes and proliferative skin diseases. In the present study, we demonstrated that 15-lipoxygenase-2 expression was increased in normal human epidermal keratinocytes and HaCaT cells treated with interferon-gamma (200 U/ml), while no induction of 15-lipoxygenase-1 was observed. Under the same culture conditions, no 15-lipoxygenase-2 was expressed by a carcinoma cell line, A431. Weak expression of 15-lipoxygenase-2 was observed in the basal cell layer of non-lesional psoriatic skin by in situ hybridization and immunostaining, whereas strong expression of 15-lipoxygenase-2 was observed in all living layers of psoriatic lesions. Actinic keratosis and squamous cell carcinomas showed a variable immunostaining pattern for 15-lipoxygenase-2. These results indicate that 15-lipoxygenase-2 is implicated in interferon-gamma-induced inflammatory processes in normal human epidermal keratinocytes and psoriatic skin.     

Calcipotriol induces apoptosis in psoriatic keratinocytes

In recent years, vitamin D3 analogues have become one of the most widely prescribed topical treatments for mild or moderate chronic plaque psoriasis. These molecules are effective and safe, but their exact mechanism of action is not completely understood. In vitro studies have shown that D3 analogues decrease proliferation and induce differentiation of keratinocytes, and have strong immunomodulating effects, but there are no conclusive data about apoptosis. The aim of this study was to evaluate differences in apoptotic response between lesional and perilesional keratinocytes of patients with psoriasis before and after treatment with calcipotriol, a synthetic vitamin D3 analogue. Keratinocytes were isolated from psoriatic plaques including lesional and perilesional skin, and cultured. Cells were treated with calcipotriol for 20 h and examined under confocal microscopy after staining with propidium iodide. The number of apoptotic cells after incubation with calcipotriol was significantly higher in lesional than in perilesional keratinocytes (P < 0.05) or non‐treated psoriatic keratinocytes (P < 0.05). In conclusion, calcipotriol seems to induce apoptosis in psoriatic keratinocytes.     

Nerve growth factor and keratinocytes: a role in psoriasis

Nerve growth factor (NGF) is synthesized and released by human keratinocytes. NGF acts as a neurotrophic molecule at the skin level, as it stimulates the sprouting of nerve fibers and regulates the synthesis and expression of neuropeptides. NGF can thus take part in neurogenic inflammation which in turn is involved in the pathogenesis of several inflammatory dermatoses. Human keratinocytes also synthesize and express the low (p75)-and the high-affinity (trk) NGF-receptor (NGF-R). NGF stimulates keratinocyte proliferation which is blocked by the natural alcaloid K252, a specific inhibitor of trk phosphorylation. K252 inhibits keratinocyte proliferation and induces keratinocyte apoptosis, in the absence of exogenous NGF, indicating the existence of an autocrine loop where NGF and trk act as key players. Finally, NGF protein levels are increased in psoriatic as compared to non-lesional and normal skin, and psoriatic keratinocytes express higher amounts of NGF than normal keratinocytes. This review will discuss the above findings in view of a possible involvement of NGF in the pathomechanisms associated with the development of the psoriatic lesion.     

New biologics for psoriasis and psoriatic arthritis

The prevalence of psoriasis is estimated to be 2.2% in the United States, and 6–39% of patients with psoriasis also develop psoriatic arthritis. New advances have been made in developing treatment options. A new human tumor necrosis factor (TNF)-α antibody, golimumab, has been shown to significantly improve symptoms of psoriatic arthritis. In addition, clinical trials of certolizumab pegol, a PEGylated Fab' fragment of an anti-TNF-α monoclonal antibody, show promising results for treating rheumatoid arthritis and suggest that it may be applicable for treating psoriasis and psoriatic arthritis in the future. New biologic therapies also include antibodies to interleukin-12 and interleukin-23. Phase II studies suggest that ustekinumab is effective in alleviating symptoms of psoriasis and psoriatic arthritis. However, longer studies with radiographic evaluation will be required before their impact on joint destruction can be assessed.     

Abnormal maturation pathway of keratinocytes in psoriatic skin

We compared the maturation pathway of normal and psoriatic epidermis using three different markers: (1) Involucrin, which is normally detected in the stratum granulosum in normal skin, was detected in all but the basal layer of involved psoriatic skin; (2) an antigen, recognized by the murine monoclonal antibody psi 3, was present in all but the basal layer of involved psoriatic skin but was absent from uninvolved and normal skin; (3) fibronectin, which normally localizes in the dermis and the epidermal-dermal junction, was also detected intra- and extracellularly in the psoriatic epidermis. These results indicate that the alterations in keratinocyte maturation found in psoriasis do not arise from a truncation of the normal maturation pathway but rather reflect the onset of an abnormal pathway of differentiation characterized by the expression of psi 3 antigen and fibronectin and the premature appearance of involucrin.     

卡泊三醇对银屑病皮损中角质形成细胞凋亡的影响

从细胞凋亡角度探讨卡泊三醇(CPT)治疗银屑病(PS)的药理机制。采用末端标记(TUNEL)技术 ,分别检测了30例CPT治疗前后的PS患者和10名正常人皮肤标本的角质形成细胞凋亡。经CPT治疗后的PS皮损中的角质形成细胞凋亡数较治疗前明显增加(P<0.05)。CPT治疗PS的疗效可能与其增加角质形成细胞的凋亡有关。     

Etanercept,a TNF antagonist for treatment for psoriatic arthritis and psoriasis

Etanercept (Enbrel, Amgen and Wyeth), a tumor necrosis factor (TNF) antagonist, was approved in January 2002, for the treatment of psoriatic arthritis (PsA). The anti-inflammatory effects of etanercept are due to its ability to bind to the pro-inflammatory cytokine TNF, preventing it from interacting with cell-surface receptors and rendering it biologically inactive. Etanercept was evaluated for the treatment of PsA and psoriasis in a preliminary study of 60 patients and in a confirmatory phase III study of 205 patients. In both studies, etanercept was shown to be significantly superior to placebo for the treatment of PsA, evaluated by Psoriatic Arthritis Response Criteria (PsARC) and American College of Rheumatology (ACR) criteria. It also was superior to placebo in improving psoriatic skin lesions, evaluated by the Psoriasis Area and Severity Index (PASI) and target lesion scores. Side-effects were minimal; mild injection site reactions, which resolved during continued therapy, were experienced by approximately one-quarter of the patients. Overall, etanercept is highly effective and well tolerated by patients with PsA, with a safety profile similar to that seen in rheumatoid arthritis.