The Expression of Psoriasin (S100A7) and CD24 Is Linked and Related to the Differentiation of Mammary Epithelial Cells

Psoriasin (S100A7), a member of the S100 family of calcium-binding proteins, is highly expressed in high-grade ductal carcinoma in situ (DCIS) and in the benign hyperproliferative skin disorder psoriasis. The gene that encodes psoriasin and many other S100 genes are located within a gene cluster on chromosome region 1q21, known as the epidermal differentiation complex. This cluster contains genes for several differentiation markers that play important roles in the terminal differentiation of the epidermis. The purpose of the present study was to evaluate the role of psoriasin in the differentiation process of mammary epithelial cells. Normal mammary epithelial cells (MCF10A) cultured in confluence and suspension, conditions known to induce psoriasin expression, demonstrated a shift towards a more differentiated phenotype indicated by an increase in the expression of the luminal differentiation markers CD24 and MUC1 and the reduced expression of the breast stem cell marker CD44. The expression of psoriasin and MUC1 was most pronounced in the CD24$^+$-enriched fraction of confluent MCF10A cells. The shift towards a more differentiated phenotype was abolished upon the downregulation of psoriasin using short hairpin RNA (shRNA) and small interfering RNA (siRNA). Using specific inhibitors, we showed that psoriasin and CD24 expression was regulated by reactive oxygen species (ROS) and the nuclear factor (NF)-κB signaling pathways. While immunohistochemical analyses of DCIS showed heterogeneity, the expression of psoriasin and CD24 showed a similar staining pattern. Our findings suggest that the expression of psoriasin is linked to the luminal differentiation marker CD24 in mammary epithelial cells. Psoriasin demonstrated an essential role in the shift towards a more differentiated CD24$^+$ phenotype, supporting the hypothesis that psoriasin plays a role in the differentiation of luminal mammary epithelial cells

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Chemokines may contribute to the systemic inflammation that is linked to the increased risk of co-morbidities in patients with psoriasis. The aim of this study was to investigate circulating chemokines in patients with psoriasis and their relationship to disease severity. Analysis of plasma levels of chemokines in patients with psoriasis before narrowband ultraviolet B (UVB) therapy revealed increased expression of Th1-associated CXCL9 and -10, Th2-associated CCL17 and CCL22, and Th17-associated CCL20. CCL20 correlated with disease severity. UVB therapy reduced skin symptoms, but did not affect the chemokine levels in plasma. Anti-CD3 and anti-CD28-mediated activation of peripheral blood mononuclear cells (PBMCs) caused a higher secretion of Th2 cytokine interleukin (IL)-13 by PBMCs from patients with psoriasis than from healthy controls. The sustained high expression of inflammatory chemokines is a potential link to systemic inflammation in psoriasis. UVB therapy may be a more effective treatment of local rather than systemic inflammation

S Gene (Corneodesmosin) Diversity and its Relationship to Psoriasis; High Content of cSNP in the HLA-Linked S Gene

Psoriasis is a heterogeneous disease in which several reports suggest the presence of a susceptibility gene in or in the proximity of the human leukocyte antigen complex in chromosome 6p. There is an association between HLA-Cw6 and young onset of the disease. The S gene (corneodesmosin), located 160 kb telomeric of HLA-C, is a strong candidate for psoriasis due to its reportedly exclusive expression in differentiating keratinocytes. We have studied this gene in a large Swedish psoriasis population and we report a strikingly high degree of polymorphism in the coding parts of the gene, 1 every 100 base pairs. We used a stratified approach to compare the polymorphic variants in patients and controls. A single nucleotide polymorphism in the coding region leading to an amino acid exchange (Ser→Phe) that differed significantly between patients and controls was identified (position 619). Owing to a high allele frequency in a larger control group, however, and an insignificant influence of the variant on the age at onset distribution curve based on a large psoriasis population, we could not confirm that this coding single nucleotide polymorphism was involved in disease etiology. We also examined the single nucleotide polymorphism in position 1243, recently proposed to have an influence on the pathogenesis of the disease. This polymorphism showed less association to the disease as compared with the single nucleotide polymorphism at positions 619 and 722. Such a high degree of variation present also in an HLA gene which is not involved in immune response indicates the difficulty involved in assessing the role of a specific allele in the pathogenesis of a complex disease in this region. A strong association effect due to linkage disequilibrium in an extended region in the HLA complex is also a complicating factor

S100A7 (Psoriasin), highly expressed in Ductal Carcinoma In Situ (DCIS), is regulated by IFN-gamma in mammary epithelial cells

<p>Abstract</p> <p>Background</p> <p>The aim of the present work was to explore signal transduction pathways used in the regulation of S100A7 (psoriasin). Members of the S100 gene family participate in many important cellular functions. Psoriasin, S100A8 (calgranulin A) and S100A9 (calgranulin B) are expressed in ductal carcinoma <it>in situ </it>(DCIS), as well as in the hyperproliferative skin disease, psoriasis. In the latter condition, a disturbance in the STAT pathway has recently been reported. This pathway is implicated in the regulation of IFN-gamma, widely recognized as a key cytokine in psoriasis. IFN-gamma also exerts anti-tumor action in a number of tumor cell types, including breast cancer. We therefore examined the effect of IFN-gamma and STAT-signaling on the psoriasin expression.</p> <p>Methods</p> <p>We established a TAC2 mouse mammary epithelial cell line with tetracycline-inducible psoriasin expression (Tet-Off). Viability in cell culture was estimated using MTS assay. Protein and gene expression were evaluated by Western blotting and quantitative real-time PCR. Statistical analyses were assessed using a one-tailed, paired t-test.</p> <p>Results</p> <p>We report the downregulation of psoriasin by IFN-gamma in the MDA-MB-468 breast cancer cell line, as well as the downregulation of psoriasin induced by anoikis in cell lines derived from different epithelial tissues. In contrast, IFN-gamma had no suppressive effect on calgranulin A or calgranulin B. IFN-gamma is an important activator of the STAT1 pathway and we confirmed an active signaling pathway in the cell lines that responded to IFN-gamma treatment. In contrast, in the SUM190 breast carcinoma cell line, IFN-gamma did not suppress the expression of endogenous psoriasin. Moreover, a reduced phosphorylation of the STAT1 protein was observed. We showed that IFN-gamma treatment and the inhibition of the transcription factor NFkappaB had a synergistic effect on psoriasin levels. Finally, in TAC2 cells with tetracycline-induced psoriasin expression, we observed the increased viability of psoriasin-expressing cells after IFN-gamma treatment.</p> <p>Conclusion</p> <p>Our data support the possibility that psoriasin expression is transcriptionally suppressed by IFN-gamma and that this effect is likely to be mediated by the activation of the STAT1 signaling pathway. The increased viability of psoriasin-expressing cells after IFN-gamma exposure suggests that psoriasin expression leads to the development of an apoptosis-resistant phenotype.</p

Collecting a set of psoriasis family material through a patient organisation; clinical characterisation and presence of additional disorders

BACKGROUND: The aim of the present study was to describe the clinical characteristics of a population of psoriatics sampled from a patient organisation and not from hospitals or out-patient clinics. Furthermore, we wanted to compare siblings with and without psoriasis regarding the occurrence of other diseases. METHODS: At the end of 1991, we initiated a project which aimed to study genetic factors leading to psoriasis. Firstly, we sent questionnaires to all the members of the Swedish Psoriasis Association. We then examined 1,217 individuals (570 with psoriasis) from 310 families, in their homes in the southern part of Sweden. All the available family members were examined clinically and asked about the course of the skin disease and the occurrence of other diseases. The eight hundred members of the proband generation were divided into two groups, with or without psoriasis, and their clinical features were compared. RESULTS: Most individuals in this study population had a mild form of psoriasis. The siblings with psoriasis had joint complaints significantly more frequently than their siblings without the skin disease and those with joint complaints had more widespread skin disease. Among the other studied concomitant diseases (iritis, heart or hypertension disease, endocrine disease, inflammatory bowel disease and neurological disease), we were not able to find any difference. Seventy-seven of 570 persons were found to be in remission (13.5%). Females had a mean onset 2.5 years earlier than males. We were not able to find any correlation between the extent of the skin disease and age at onset. Twice as many persons with joint complaints were found among those with psoriasis than among those without, 28% versus 13%. Almost half (48%) the psoriatics who also had joint complaints had psoriasis lesions on their nails. Endocrine disorders were found in 9% of those without any allele for Cw6, but only in 1% of those who had Cw6. In fact, none of 183 Cw6 carriers had diabetes, as compared to the population prevalence of 3–5% in Sweden. CONCLUSION: With the exception of joint complaints, persons with psoriasis, collected from a patient organisation, did not have an increased frequency of (studied) co-existing diseases

Genetic studies on psoriasis with emphasis on the HLA-region

In collaboration with the Swedish Psoriasis Association, a large patient sample has been collected with blood samples for DNA analysis. The main purpose of the group has been to demonstrate the genetic contribution to the disease and to localise susceptibility genes. Psoriasis is a heterogeneous disease in which several reports suggest the presence of a susceptibility gene in or in the proximity of the HLA complex in chromosome 6p. There is an association between HLA-Cw6 and young onset of the disease. The aim of this study was to evaluate the importance of HLA and in particular the Cw6 allele in the development of psoriasis. We could confirm the presence of a gene in the HLA region by means of parametric and non parametric linkage analysis in 104 families. Using the Transmission Disequilibrium Test, (TDT), which is a statistical association test, we found further support for this.We used a PCR-based typing method for Cw6 and showed a strong association to young onset of the disease. We studied the age at onset of siblings discordant for the presence of Cw6 using the Wilcoxon signed rank test. This test was significant with a mean difference in age at onset of 8 years. The Cw6 allele was sequenced in individuals homozygous for Cw6 without finding any alterations from the consensus reference sequence. In all, 11 individuals homozygous for Cw6 were identified by a sequencing method. They had an earlier age at onset than heterozygotes, which we interpret as a tendency to a gene dose effect. We found support for the direct influence of Cw6 on age at onset, rather than a polygenic effect where every genetic component adds to the genetic load. The S gene (corneodesmosin), located 160 kb telomeric of HLA-C, is a strong candidate for psoriasis due to its reportedly exclusive expression in differentiating keratinocytes. We found a high variability in the coding parts of the gene using sequencing analysis. We performed association tests such as TDT and case control analysis, and compared several polymorphisms among patients and controls using a stratification approach, in order to decrease the influence of heterogeneity and population differences. Based on TDT results of polymorphisms in the S gene, multiallelic markers in the HLA region and from the Cw6 allele per se, we conclude that Cw6 is likely to be the primary association in this region. However, further studies are required to evaluate if Cw6 itself or a gene in linkage disequilibrium with Cw6 is the factor in the HLA region determining age at onset.We have also performed cytogenetic analysis of 477 unrelated psoriatics. We found 2 patients with a translocational breakpoint in 11q12-13, in a region where the major atopy locus as well as a locus for diabetes mellitus is located. The breakpoints were further characterised by fluorescent in situ hybridisation

Involved and Uninvolved Psoriatic Keratinocytes Display a Resistance to Apoptosis that may Contribute to Epidermal Thickness

Psoriasis is a common autoimmune skin disease. The aim of this study was to investigate whether the apoptotic process is disturbed in psoriatic keratinocytes. In vitro culture of keratinocytes derived from both involved and uninvolved psoriatic skin, revealed higher viability and resistance to apoptosis following exposure to ultraviolet B, compared with cells from healthy controls. The position of apoptotic dysregulation was found to be upstream of cytochrome c release in the mitochondrial apoptotic pathway. Microarray transcriptome analysis revealed that 87 genes were differentially expressed in both involved and uninvolved psoriatic keratinocytes compared with controls. Among these, a general upregulation of anti-apoptotic genes and downregulation of pro-apoptotic genes were identified. This distinct apoptosis-resistant phenotype, unrelated to the inflammatory component of the disease, implies that intrinsic abnormalities in keratinocytes may contribute to the pathogenesis of psoriasis.Funding Agencies|Swedish Research Council; Ingrid Asp Foundation; Welander Foundation; Swedish Psoriasis Association</p