Psoriasis is a common chronic skin disease, affecting ∼2% of the world’s population (Nestle et al., 2009). It is a chronic skin disease characterized by hyperproliferation of epidermal cells with prominent blood vessels and perivascular lymphocytic infiltrates. Clinically, psoriasis manifests as dry red, raised, scaly plaques and may be several centimeters in diameter. Usually, the skin is covered with many individual lesions, separated by normal-appearing skin, but in severe cases the whole skin can be affected. The histopathological changes that distinguish psoriasis from other inflammatory skin diseases are keratinocyte hyperproliferation (acanthosis) with loss of the granular cell layer, regular elongation of the rete ridges, hyperkeratosis, parakeratosis, infiltration of many different leukocytes and increased vascularity in the dermis (Creamer et al., 2002; Bologna et al., 2003).
In psoriasis, activated T-cell subsets localize to the dermis and epidermis and initiate a local inflammatory reaction that leads to the development of a psoriatic plaque (Griffiths and Barker, 2007).
Common triggers of angiogenesis in psoriasis include epidermal barrier disruption and hypoxia. These trigger the release of proangiogenic cytokines from keratinocytes, which are vascular endothelial growth factor (VEGF), basic fibroblast growth factor, tumor necrosis factor (TNF), transforming growth factor-α and interleukins (IL-17 and IL-18) (Elias et al., 2008; Heidenreich et al., 2009).
Abnormal capillaries become dilated, before keratinocyte hyperplasia, early in the development of psoriatic lesions. After successful antipsoriasis treatment, resolution of microvascular dilatation precedes resolution of acanthosis, but the convoluted capillaries remain apparent in the upper dermis for up to 9 months after lesions resolve clinically (De Angelis et al., 2002).
The active form of VEGF is a 40–45 kDa homodimeric glycoprotein. It is a major regulator of physiological and pathological angiogenesis. The receptors for VEGF (VEGFR-1 or VEGFR-2) are primarily expressed by vascular endothelial cells (ECs) (Heidenreich et al., 2009).
VEGF is also known as the vascular permeability factor as it has the ability to induce vascular leakage. It is well established that such permeability-enhancing activity underlies the significant role of this molecule in inflammation (Ferrara et al., 2003). In psoriatic skin, VEGFR-1 and VEGFR-2 are detectable and functional in keratinocytes. VEGF may also contribute to keratinocyte hyperproliferation in psoriasis in an autocrine manner (Man et al., 2006).
Epidermal VEGF production is required for permeability barrier homeostasis, dermal angiogenesis, and for the development of epidermal hyperplasia. Epidermis-localized VEGF-a−/− knockout mice demonstrated abnormal permeability barrier homeostasis and marked reduction in the density of the microvasculature in the papillary dermis; vascular permeability was markedly impaired and they did not develop epidermal hyperplasia in response to repeated external trauma (Elias et al., 2008).
The growth of keratinocytes is regulated by a delicate balance between molecules that control cell survival and cell death (Man et al., 2006). In psoriasis this regulation is disturbed, leading to keratinocyte hyperproliferation (Hussein et al., 2004).
Survivin is the smallest member of the gene family of inhibitors of apoptosis. Low levels of survivin might be necessary to preserve the regenerative potential of epidermal stem cells and protect keratinocytes from important environmental insults such as ultraviolet light-induced apoptosis (Xu et al., 2004). Further, it has been postulated that survivin is not completely absent in mature adult tissue – it is only downregulated (Abdou and Hanout, 2008). In addition to the antiapoptotic functions, it also regulates the cell cycle in keratinocytes. Survivin is mostly detected in the nucleus of keratinocyte stem cells; however, it is also expressed in melanocytes and fibroblasts (Dallaglio et al., 2011).
Blockage of the normal apoptotic process is one of the factors implicated in the pathogenesis of psoriasis. The Bcl-2 gene is located on chromosome 18 and encodes an inner mitochondrial protein that protects cells from apoptosis by binding to the bax protein. Overexpression of bcl-2 can counter the physiologically relevant signals of apoptosis. In normal skin, bcl-2 expression is confined to the germinative basal compartment (Chiodino et al., 1999).
iNOS is a nitric oxide (NO) synthase induced after a stimulus. In psoriasis, a significant increase in the expression of iNOS has been detected in lesional skin compared with healthy skin. In-situ hybridization and immunohistochemical studies identified iNOS mRNA and protein in the epidermal keratinocytes of psoriatic lesions (Shimizu et al., 1997).
It has been reported that low levels of NO induce keratinocytes proliferation, whereas higher levels can block this proliferation and trigger cell differentiation, even in keratinocytes. In psoriasis, hyperproliferation of keratinocytes occurs despite the marked overexpression of iNOS (Suschek et al., 2004). It has been suggested that a competitive activity of arginase-1 activity, an enzyme highly expressed in psoriasis, reduces the arginine available to NOS, thus limiting NO production (Bruch-Gerharz et al., 2003).
VEGF promotes the survival of ECs, inducing the expression of antiapoptotic effector molecules, such as survivin, in ECs (Tran et al., 2002).
The relationship between NO and VEGF has been reported (Dembinska-Kiec et al., 1997; Brennan et al., 2002). Ziche et al. (1997) studied the upstream signal of NO for VEGF-related kinases.
Materials and methods
This study was conducted on 30 cases of psoriasis obtained from the Dermatology and Andrology Clinic, Faculty of Medicine, Zagazig University, Egypt, between April 2010 and March 2011. Punch biopsies were taken from the patients, and 10 biopsies obtained from normal individuals without a family history of psoriasis were used as control specimens. A written informed consent was taken from both patients and controls before taking the biopsy. None of the patients were receiving systemic or phototherapy. All topical therapies, apart from emollients, were discontinued 3 weeks before entry into the study. All biopsies were submitted for histopathological evaluation to confirm the diagnosis of psoriasis and for immunohistochemical staining for VEGF, iNOS, bcl-2 and survivin antibodies in the Pathology Department, Faculty of Medicine, Zagazig University, Egypt.
Immunohistochemical staining was carried out using the streptavidin–biotin immunoperoxidase technique (DakoCytomation, California, USA). Sections of 3–5 μm thickness, cut from formalin-fixed paraffin-embedded blocks, were deparaffinized in xylene and rehydrated in graded alcohol. Sections were boiled in citrate buffer (pH 6.0) for 20 min and then washed in phosphate buffer saline (pH 7.3). Thereafter, blocking of endogenous peroxidase activity with 6% H2O2 in methanol was carried out. The slides were then incubated overnight with the monoclonal antibodies anti-VEGF (dilution 1 : 200; Santa Cruz Biotechnology, California, USA), anti-survivin (dilution 1 : 10; Santa Cruz Biotechnology), anti-bcl-2 oncoprotein (6 ml, clone bcl-2/100, IgG1 kappa, code number AM287-5M; BioGenx, California, USA) and anti-iNOS (dilution 1 : 50; Santa Cruz Biotechnology). Negative controls, obtained by substitution of primary antibodies with blocking buffer, were included in the staining procedure. Incubation with a secondary antibody and product visualization were performed (DakoCytomation, Glostrup, Denmark) with diaminobenzidine substrate as the chromogen. The slides were finally counterstained with Mayer’s haematoxylin.
Assessment of immunostaining
Cytoplasmic immunostaining for VEGF, bcl-2 and iNOS was semiquantitatively scored as follows: 0, negative; 1, weak (<10% expression of cells); 2, moderate (10–20% expression of cells); and 3, strong (expression in >50%). A score of 2 or higher was considered positive (Ross et al., 2005).
For semiquantification of survivin expression, a score was obtained by multiplying the intensity of the staining by the size of the area that stained positively. The intensity of cell staining was graded according to the following scale: 0, no staining; 1, mild staining; 2, moderate staining; and 3, marked staining. The area of staining was evaluated on the following scale: 0, 10% of cells stained positive; 1, 10–30% of cells stained positive; 2, 30–70% of cells stained positive; and 3, more than 70% of cells stained positive. The maximum combined score was 9, and the minimum was 0. Specimens with scores of 3 or more were considered positive for survivin expression (Moon and Tarnawski, 2003).
The results of the study were statistically analyzed using the SPSS version 15 statistical program. Data were expressed as mean±SD for quantitative variables, as numbers and percentages. For categorical variables, the Student t-test was used. Correlation (r) was used to find the relationship between quantitative variables. P-value less than 0.05 was considered significant.
The psoriatic group included 15 male and 15 female patients; their ages ranged from 11 to 70 years with a mean of 43.2±16.75 years. The duration of their disease varied from 1 to 140 months with a mean of 50.4±40.08 months (Table 1).
Evaluation of vascular endothelial growth factor immunostaining
In psoriasis there was strong cytoplasmic VEGF expression throughout the epithelium (mean 46.1±19.66) and moderate expression in inflammatory infiltrates and blood vessels (mean 19±5.4 and 8.0±2.16, respectively). In contrast, in healthy skin, VEGF expression was faint (mean 0.92±0.18) (Table 2, Fig. 1a). VEGF was significantly upregulated in psoriatic specimens compared with normal healthy skin (P<0.0001).
Evaluation of survivin immunostaining
Out of 30 psoriatic lesions, 24 (80%) showed positivity for survivin. The staining was seen either in the epidermis or in the endothelium of proliferating capillaries, or in both. Pure epidermal staining, either diffuse or focal, was seen in 14 cases (58.34%), whereas endothelial staining was seen in four cases (16.67%). Moreover, six cases (25%) showed both epidermal and endothelial staining.
Nuclear survivin expression was seen mainly in the psoriatic epithelial suprabasal layers. Whereas cytoplasmic expression was seen in the basal and suprabasal keratinocytes, in the dermis, cytoplasmic survivin staining was strong and diffuse in the vessel walls (Fig. 2b). In normal skin, epidermal survivin expression was mostly negative, but a faint stain appeared in the epithelial basal layer (Fig. 2a) and in capillary ECs. Staining of the outer root sheath of hair follicles and sweat glands was also observed in normal specimens.
Survivin was significantly upregulated in psoriatic specimens in comparison with healthy controls (P<0.0001) (Table 3).
Evaluation of BCL-2 immunostaining
Bcl-2 immunostaining was identified in all cases of normal skin (100%) and in 16/30 cases (53.3%) of psoriatic skin (Fig. 3a and b). The expression was predominantly mild or weak in psoriatic patients and strong in the basal layer of the normal epidermis. The suprabasal keratinocytes were uniformly Bcl-2 negative in psoriatic and normal skin samples. Bcl-2 protein expression was significantly decreased in psoriatic skin samples, as compared with normal skin (P<0.05).
Evaluation of iNOS immunostaining
iNOS expression was significantly increased in the cytoplasm of psoriatic epidermis and dermis compared with healthy skin (P<0.0001). There is a modest iNOS expression in the psoriatic vessel wall (Table 4, Fig. 4b).
Correlation between vascular endothelial growth factor and survivin
In psoriasis a significant positive correlation between VEGF and survivin expression (r=0.83) was found (Fig. 5a).
Correlation between epithelial vascular endothelial growth factor and iNOS
In psoriasis a significant positive correlation between VEGF and iNOS expression (r=0.793) was found (Fig. 5b, Table 5).
Evidence indicates that the cellular immune system plays a major role in the maintenance of dermal inflammation and epidermal proliferation. This is supported by the predominant infiltration into the dermis and epidermis by CD4(+)-activated and CD8(+)-activated T cells, respectively (Baker and Fry, 1992). In this study we explored the role of apoptosis inhibitors survivin and bcl-2, as well as that of VEGF and iNOs, in the pathogenesis of psoriasis.
In psoriasis, there is active hyperproliferation of keratinocytes and abnormal vascular expansion within the superficial dermis. This expansion is mediated by angiogenesis, an active vasoproliferative process that appears to be a key inflammatory response early in the pathogenesis of psoriasis (Hern et al., 2005).
In psoriasis we detected a strong VEGF expression throughout the epithelium (mean 46.1±19.66) and moderate expression in inflammatory infiltrates and blood vessels (mean 19±5.4 and 8.0±2.16, respectively). This is in agreement with the study by Detmar et al. (1994), who found that the immunohistochemistry of psoriatic skin reveals strong cytoplasmic VEGF staining predominantly in suprabasal epidermal keratinocytes and in the papillary dermal microvessels of active psoriatic lesions. Further, Simonetti et al. (2009) found that VEGF was strongly expressed in psoriasis throughout the epithelium (mean 45.60±19.84) and moderately in the inflammatory infiltrates and vessels (mean 21.50±10.75 and 8.40±2.84, respectively). VEGF appears to act not only on ECs but also on keratinocytes to induce the psoriasiform phenotype, including acanthosis, parakeratosis subepidermal inflammatory infiltrate, tortuous and dilated dermal capillaries, and epidermal microabscesses.
VEGF has been shown to upregulate the expression of cell adhesion molecules from sprouting capillaries and to increase vessel permeability, thereby allowing enhanced migration of leukocytes into psoriatic skin (Detmar et al., 1998).
Avramidis et al. (2010) found that the mean VEGF expression in ECs and in the dermis was 30.82±0.65 in psoriatic skin and they reported reduction in VEGF expression by 81.6% at week 10 under etanercept treatment.
In contrast, in healthy skin we noted faint VEGF expression (mean 0.92±0.18), a finding that is in agreement with that of Detmar et al. (1994), who reported little or no VEGF receptor expression in the deeper vessels of psoriatic skin or in vessels of normal skin. Moreover, it is in agreement with the results of Simonetti et al. (2009).
VEGF was significantly upregulated in psoriatic specimens in comparison with normal healthy skin (P<0.0001).
Keratinocyte-derived VEGF probably actively contributes to the pathogenesis of psoriasis through the induction of permeability in dermal vessels, its chemotactic action on inflammatory cells and ECs, and its angiogenic effect (Detmar et al., 1998). VEGF increases keratinocyte mitosis in vitro and upregulates the expression of VEGFR-1 and VEGFR-2 on both keratinocytes and ECs. This autocrine/paracrine loop appears to contribute to the cycle of angiogenesis and epidermal hyperplasia in psoriasis (Armstrong et al., 2011).
Psoriasis is a common inflammatory skin disease showing many pathological features, including the presence of marked T-cell infiltrates, hyperplasis/altered differentiation of keratinocytes, and infiltration by a group of CD11c+/CD1a+ dendritic cells (DCs) that have been termed inflammatory dendritic epidermal cells (De Jongh et al., 2005). Advanced work in psoriasis has also identified skin infiltration by a group of CD11c+ cells, DCs that synthesize TNFα-producing and iNOS-producing cells (TIP-DCs). These cells are evident in both the dermis and epidermis and are a major cell type in psoriatic skin (Lowes et al., 2005).
In our study iNOS expression was significantly increased (P<0.0001) in the psoriatic epithelium and dermis compared with normal skin. We observed a moderate expression of iNOS in the psoriatic vessel walls; these findings are commensurate with the findings of Detmar et al. (1998).
Nomura et al. (2003) detected a significant increase in iNOS expression in psoriasis compared with atopic dermatitis (P<0.016).
Overexpression of iNOS contributes to VEGF-induced angiogenesis (Kroll and Waltenberger, 1998). Moreover, VEGF mediates a central part of its proangiogenic effect through stimulation of eNOS and possibly iNOS-derived NO (Tran et al., 2002). In our study we observed a significant positive correlation between VEGF and iNOS expression (r=0.793). This result agrees with that of Simonetti et al. (2009), who found a significant positive correlation between VEGF and iNOS expression (r=0.733, P=0.038).
We observed an absence of survivin staining in the suprabasal layers in control specimens, and its confinement to the basal layer of the epidermis was similar to the findings of Abdou and Hanout (2008) and Chiodino et al. (1999). The basal layer of the epidermis represents a population of stem cells that have a high capacity for self-renewal and it is responsible for constant epidermal turnover. Basal keratinocytes have an autocrine survival system protecting them from apoptosis through inhibition of the caspase pathway (Chiodino et al., 1999). However, no survivin immunostaining was detected in normal skin according to Bowen et al. (2004). Faint survivin expression in the epithelial basal layer and in capillary ECs was detected by Simonetti et al. (2009).
Out of 30 psoriatic lesions, 24 (80%) showed positivity for survivin, comparable to the findings of Bowen et al. (2004), which reached 88%, and those of Abdou and Hanout (2008), which reached 73%. These differences are due to the different numbers of investigated psoriatic cases in each study.
In our study, survivin was significantly upregulated in psoriatic specimens in comparison with normal skin (P<0.0001). We detected nuclear survivin expression mainly in the psoriatic epithelial suprabasal layer, whereas cytoplasmic survivin expression was seen in the basal and suprabasal keratinocytes. These results were similar to those of Simonetti et al. (2009).
In this study, the endothelial pattern of staining was seen in 10/24 (41.67%) psoriatic lesions, whereas it was not observed in control specimens. This is consistent with the results of Abdou and Hanout (2008).
The endothelium is one of the most critical sites for control of apoptosis in many situations, such as vascular injury, vascular remodeling and new blood vessel formation (angiogenesis). VEGF and basic fibroblast growth factor maintain EC viability by induction of the antiapoptotic machinery system in ECs, including survivin expression (O’Connor et al., 2000).
We detected Bcl-2 expression confined mainly to the basal cell layer and the outer root sheath, as shown in some previous studies (Kocak et al., 2003), protecting the proliferative compartment from apoptotic stimuli (Takahashi et al., 2002). Expression of the Bcl-2 protein was significantly decreased in psoriatic skin, which was in accordance with minimal or absent Bcl-2 expression detected by previous studies (Tomkova et al., 1997; Kocak et al., 2003). This unexpected finding could be the result of increased p53 protein expression in involved psoriatic skin and suggests that Bcl-2 plays no role in the antiapoptotic mechanisms proposed to operate in psoriasis.
Psoriasis may develop not only as a consequence of excessive cell proliferation but may also be the result of prolonged cell survival. The antiapoptotic factor bcl-2 was downregulated in psoriatic lesions in comparison with normal skin. It was proposed that bcl-2 had no major role in psoriasis, and, except for bcl-x, the primary contributory role of the bcl family of proteins in the pathogenesis of psoriasis is highly doubted (Kocak et al., 2003). However, in our study, upregulation of survivin in psoriatic lesions in comparison with normal skin was evident (P<0.0001), suggesting its role in the pathogenesis of psoriasis. The targeted therapy directed against TNFα (infliximab) reduces survivin expression and produces marked clinical response in the skin and joints of psoriatic patients (Markham et al., 2006). In Markham et al.’s (2006) study, a differential expression of survivin was found between keratinocytes and ECs, agreeing with our findings.
In our study we found a significant positive correlation between the expression of VEGF and survivin (r=0.83, P<0.001). This means that there are synergistic effects between them during the development of psoriasis, and there was also a positive correlation between the expression of VEGF and survivin (P<0.05) in hepatocellular carcinoma, as seen in the study by Zhu et al., 2003.
The antiapoptotic role of survivin was evident from its expression in not only the epidermis but also in ECs of the proliferating capillaries of the papillary dermis. VEGF promotes survival of ECs through induction of survivin. VEGF, survivin and iNOS appeared to be important factors in the pathogenesis of psoriasis; however, BCL-2 plays no role in the antiapoptotic mechanisms in psoriasis. Further genetic studies will be needed to confirm these findings. Novel and selective therapeutic strategies in the treatment of psoriasis may be developed on this basis.
Conflicts of interest
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