GLI Transcriptional Targets S100A7 and KRT16 Show Upregulated Expression Patterns in Epidermis Overlying the Tumor Mass in Melanoma Samples.

Although not completely understood, the role of the Hedgehog-GLI (HH-GLI) signaling pathway in melanoma and epithelial skin tumors has been reported before. In this study, we confirmed in various melanoma cell line models that keratin 16 (KRT16) and S100 Calcium-Binding Protein A7 (S100A7) are transcriptional targets of GLI Family Zinc Finger (GLI) proteins. Besides their important role in protecting and maintaining the epidermal barrier, keratins are somehow tightly connected with the S100 family of proteins. We found that stronger expression of KRT16 indeed corresponds to stronger expression of S100A7 in our clinical melanoma samples. We also report a trend regarding staining of GLI1, which corresponds to stronger staining of GLI3, KRT16, and S100A7 proteins. The most interesting of our findings is that all the proteins are detected specifically in the epidermis overlying the tumor, but rarely in the tumor itself. The examined proteins were also not detected in the healthy epidermis at the edges of the sample, suggesting that the staining is specific to the epidermis overlaying the tumor mass. Of all proteins, only S100A7 demonstrated a statistically significant trend regarding tumor staging and staining intensity. Results from our clinical samples prove that immune infiltration is an important feature of melanoma. Pigmentophages and tumor-infiltrating lymphocytes (TIL) demonstrate a significant association with tumor stage, while mononuclear cells are equally present in all stages. For S100A7, we found an association between the number of TILs and staining intensity. Considering these new findings presented in our study, we suggest a more detailed examination of the possible role of the S100A7 protein as a biomarker in melanoma.

GPR15LG regulates psoriasis-like inflammation by down-regulating inflammatory factors on keratinocytes.

Psoriasis is a common chronic inflammatory skin disease characterized by aberrant proliferation of keratinocytes and infiltration of immune cells. We previously found that GPR15LG protein is highly expressed in psoriasis lesional skin and it positively regulates psoriatic keratinocyte proliferation. Our data also showed that GPR15LG could regulate the activity of NF-κB pathway, which is associated with psoriatic inflammation. In the present study, we demonstrated that Gpr15lg (ortholog of GPR15LG) knockdown attenuated the severity of imiquimod (IMQ)-induced psoriasis-like inflammation in mice. Such an effect was achieved by down-regulating the expression of inflammatory cytokines interleukin (IL)-1α, IL-1ß, tumor necrosis factor (TNF)-α and S100A7. Consistently, GPR15LG knockdown in vitro significantly downgraded the expression of inflammatory factors in the cellular model of psoriasis. These results suggested that GPR15LG could be involved in the development of psoriasis by regulating inflammation.

Mutagenesis of the Loop 3 α-Helix of Neisseria gonorrhoeae TdfJ Inhibits S100A7 Binding and Utilization.

Neisseria gonorrhoeae causes the sexually transmitted infection (STI) gonorrhea, which afflicts over 80 million people each year. No vaccine is available to prevent gonorrhea. The pathogen alters the expression and antigenic presentation of key surface molecules, making the identification of suitable vaccine targets difficult. The human host utilizes metal-binding proteins to limit free essential transition metal ions available to invading pathogens, limiting their infective potential, a process called nutritional immunity. To overcome this, N. gonorrhoeae employs outer membrane TonB-dependent transporters (TdTs) that bind host nutritional immunity proteins and strip them of their metal cargo. The TdTs are well conserved, and some play key roles in establishing infections, making them promising vaccine targets. One TdT, TdfJ, recognizes human S100A7, a zinc-binding protein that inhibits the proliferation of other pathogens via zinc sequestration. N. gonorrhoeae uses TdfJ to strip and internalize zinc from S100A7. TdfJ contains a conserved α-helix finger in extracellular loop 3; a similar α-helix in loop 3 of another gonococcal TdT, TbpA, plays a critical role in the interaction between TbpA and human transferrin. Therefore, we hypothesized that the TdfJ loop 3 helix (L3H) participates in interactions with S100A7. We determined the affinity between wild-type TdfJ and S100A7 and then generated a series of mutations in the TdfJ L3H. Our study revealed that mutagenesis of key residues within the L3H reduced S100A7 binding and zinc piracy by the gonococcus, with profound effects seen with substitutions at residues K261 and R262. Taken together, these data suggest a key role for the TdfJ L3H in subverting host metal restriction. IMPORTANCE Gonorrhea is a global threat to public health due to the increasing incidence of antimicrobial drug resistance, rising treatment costs, and lack of a protective vaccine. The prospect of untreatable gonococcal infections has spurred efforts to identify targets for novel therapeutic and prevention strategies, and members of the family of outer membrane TonB-dependent metal transporters have emerged as promising candidates. These conserved surface molecules play a critical role in establishing infection by facilitating nutrient uptake in the human host that dedicates considerable efforts to restricting nutrient availability. In this study, we characterized the binding interaction between the zinc importer TdfJ and its human zinc source, S100A7. We went on to identify a key region of TdfJ that mediates this interaction. With a more thorough understanding of the intricate relationships between these bacterial nutrient receptors and their host nutrient sources, we may help pave the way toward identifying effective prophylaxis and treatment for an important human disease.

High S100A7 expression is associated with early muscle invasion and poor survival in bladder carcinoma.

Muscle-invasive bladder carcinoma (MIBC) accounts for 25% of newly diagnosed bladder carcinomas (BCs) and presents a high risk of progression and metastasis. This study aimed to identify reliable biomarkers associated with muscle invasion and prognosis to identify potential therapeutic targets for MIBC. Four gene datasets were downloaded from the Gene Expression Omnibus, and the integrated differentially expressed genes (DEGs) were then subjected to gene ontology (GO) terms and pathway enrichment analyses. Correlation analysis between the expression of the top-ranking DEGs and pathological T stages was performed to identify the genes associated with early muscle invasion. The corresponding prognostic values were evaluated, and co-expressed genes mined in the cBioPortal database were loaded into ClueGo in Cytoscape for pathway enrichment analysis. Using data mining from the STRING and TCGA databases, protein-protein interaction and competitive endogenous RNA networks were constructed. In total, 645 integrated DEGs were identified and these were mainly enriched in 26 pathways, including cell cycle, bladder cancer, DNA replication, and PPAR signaling pathway. S100A7 expression was significantly increased from the T2 stage and showed significantly worse overall survival and disease-specific survival in patients with BC. In total, 144 genes co-expressed with S100A7 in BC were significantly enriched in the IL-17 pathway. S100A7 was predicted to directly interact with LYZ, which potentially shows competitive binding with hsa-mir-140 to affect the expression of six lncRNAs in MIBC. In conclusion, high S100A7 expression was predicted to be associated with early muscle invasion and poor survival in patients with BC.

LncRNA MALAT-1 regulates the growth of interleukin-22-stimulated keratinocytes via the miR-330-5p/S100A7 axis.

Psoriasis is a chronic autoimmune disorder related to abnormal keratinocyte proliferation. Long noncoding RNAs (lncRNAs) are significant regulators in the progression of skin diseases. In this study, we explored how lncRNA MALAT-1 controls the pathogenesis of psoriasis by examining its impact on keratinocyte proliferation, inflammation, and apoptosis. A psoriasis cell model was established by treating HaCaT keratinocytes with the inflammatory factor, IL-22 (100 ng/ml), for 24 h. The MALAT-1 and S100A7 levels in psoriatic lesions, normal skin tissues, and IL-22-stimulated HaCaT cells were determined by RT-qPCR and western blotting. Cell proliferation, inflammation, and apoptosis were detected by the MTT assay, western blotting, and flow cytometry analysis, respectively. Bioinformatics analysis was used to identify the miRNAs that bind to MALAT-1 and S100A7. The relationships between MALAT-1 or miR-330-5p and S100A7 were assessed using a luciferase reporter assay. The MALAT-1 and S100A7 levels were upregulated in both psoriatic lesion samples and IL-22-stimulated HaCaT cells. Silencing MALAT-1 significantly reversed the IL-22-stimulated promotion of HaCaT proliferation and changes in Ki67 and KRT5/14/1/10 protein levels, and MALAT-1 deficiency also reversed the upregulation of TNF-α, IL-17, and IL-23 protein levels as well as suppression of cell apoptosis. As a ceRNA, MALAT-1 competed with S100A7 to prevent miR-330-5p-induced inhibition of S100A7 expression. There was a negative correlation between miR-330-5p and MALAT-1 (or S100A7) expression in psoriatic lesion tissues. In response to IL-22 treatment, miR-330-5p silencing eliminated the effects of MALAT-1 knockdown in HaCaT cells. Thus, these findings demonstrated that MALAT-1 modulates the IL-22-induced changes in HaCaT cells through the miR-330-5p/S100A7 axis.

Desensitization of human breast progenitors by a transient exposure to pregnancy levels of estrogen.

Full term pregnancy at an early age is the only factor known to consistently protect against breast cancer. Because hormone receptor positive progenitors in the human breast relay endocrine signaling, we here sought to determine whether an experimental mimicry of the third trimester surge of hormones would change their susceptibility to growth stimulation. Hormone receptor positive, reduction mammoplasty-derived human breast epithelial progenitors were exposed to a short-term, pregnancy-level of estradiol, and their subsequent response to estradiol stimulation was analyzed. Exposure to pregnancy-level of estradiol results in subsequent lower sensitivity to estrogen-induced proliferation. Expression array and immunoblotting reveal upregulation of S100A7 and down-regulation of p27, both associated with parity and epithelial differentiation. Notably, we find that the epithelial differentiation is accompanied by upregulation of E-cadherin and down-regulation of vimentin as well as by diminished migration and more mature luminal epithelial differentiation in a mouse transplantation model. Our findings are in support of a de-sensitization mechanism for pregnancy-induced prevention against breast cancer.

S100A7 as a potential diagnostic and prognostic biomarker of esophageal squamous cell carcinoma promotes M2 macrophage infiltration and angiogenesis.

Dysregulated expression of S100A7 is found in several cancers and plays an important role in tumor progression; however, its carcinogenic role in esophageal squamous carcinoma (ESCC) is still poorly understood. Here, we identified that the levels of S100A7 were remarkably upregulated in 341 tumor tissues (P < .001) and 274 serum samples (P < .001) of ESCC patients compared with normal control. It was an independent prognostic factor (P = .026). Furthermore, a new diagnostic model for ESCC based on serum S100A7, SCC, and crfra21-1 was established with area under curve (AUC) up to 0.863 (95% CI: 0.802-0.925). Mechanically, we found upregulated S100A7 could promote cell migration and proliferation through intracellular binding to JAB1 and paracrine interaction with RAGE receptors and then activates the downstream signaling pathways. In addition, exocrine S100A7 could promote M2 macrophage infiltration and polarization by up-regulating M2 macrophage associated proteins, and tumor angiogenesis by enhancing the activation of p-ErK and p-FAK pathways. Further animal experiments confirmed the role of S100A7 in promoting M2 macrophage infiltration and angiogenesis in ESCC. In conclusion, these findings highlighted the potential diagnostic and prognostic value of S100A7 in patients with ESCC. Meanwhile, our results reveal that S100A7 promotes tumor progression by activating oncogenic pathways and remodeling tumor microenvironment, which paving the way for the progress of S100A7 as a therapeutic target for cancer treatment.

Antimicrobial peptides in human corneal tissue of patients with fungal keratitis.

BACKGROUND: Fungal keratitis (FK) is the leading cause of unilateral blindness in the developing world. Antimicrobial peptides (AMPs) have been shown to play an important role on human ocular surface (OS) during bacterial, viral and protozoan infections. In this study, our aim was to profile a spectrum of AMPs in corneal tissue from patients with FK during the active pase of infection and after healing. METHODS: OS samples were collected from patients at presentation by impression cytology and scraping. Corneal button specimens were collected from patients undergoing therapeutic penetrating keratoplasty for management of severe FK or healed keratitis. Gene expression of human beta-defensin (HBD)-1, -2, -3 and -9, S100A7, and LL-37 was determined by quantitative real-time PCR. RESULTS: Messenger RNA expression (mRNA) for all AMPs was shown to be significantly upregulated in FK samples. The levels of HBD-1 and -2 mRNA were found to be elevated in 18/20 FK samples. Whereas mRNA for HBD-3 and S100A7 was upregulated in 11/20 and HBD9 was increased in 15/20 FK samples. LL-37 mRNA showed moderate upregulation in 7/20 FK samples compared with controls. In healed scar samples, mRNA of all AMPs was found to be low and matching the levels in controls. CONCLUSION: AMP expression is a consistent feature of FK, but not all AMPs are equally expressed. HBD-1 and -2 are most consistently expressed and LL-37 the least, suggesting some specificity of AMP expression related to FK. These results will help to identify HBD sequence templates for designing FK-specific peptides to test for therapeutic potential.

Serum Concentration and Skin Expression of S100A7 (Psoriasin) in Patients Suffering from Hidradenitis Suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease. An important role of innate immune dysregulation in the pathogenesis of HS has been highlighted. S100A7 (psoriasin) is an innate, antimicrobial protein that exerts proinflammatory and chemotactic action. OBJECTIVES: The objective of the study was to investigate serum concentrations of S100A7 in individuals with HS as compared to healthy controls. Further, we evaluated the expression of S100A7 in lesional HS skin as compared to perilesional (clinically uninvolved) HS skin and normal skin. METHODS: Serum concentrations of S100A7 were evaluated with a commercially available ELISA kit. The expression of S100A7 in the skin was assessed using qRT-PCR and immunofluorescence staining. RESULTS: We found increased expression of S100A7 in lesional HS skin as compared to perilesional HS skin (p = 0.0017). The expression of S100A7 in lesional HS skin was positively associated with serum C-reactive protein concentration and the severity of disease according to Hurley staging. The serum concentration of S100A7 in individuals with HS was decreased as compared to healthy controls and patients with psoriasis. CONCLUSIONS: Upregulated in lesional HS skin, S100A7 may enhance the inflammatory process and contribute to the HS pathogenesis.

Interleukin-17A suppresses granular layer formation in a 3-D human epidermis model through regulation of terminal differentiation genes.

Immunotherapies targeting interleukin (IL)-17 greatly improve plaque psoriasis. Most previous studies on IL-17 focused on the T-helper (Th)17 immune response, but investigation of the effects of IL-17A on psoriatic epidermal structure are limited. Using an in vitro 3-D human epidermis model, we investigated the effects of IL-17A and IL-17C on morphological changes and gene expression. IL-17A directly suppressed the formation of the granular layer, whereas IL-17C did not. IL-17A significantly downregulated the gene expression of profilaggrin (FLG), which is a major component of keratohyalin granules in the granular layer. Global gene expression analysis of this 3-D epidermis model showed that both IL-17A and IL-17C upregulated S100A7A and type 1 interferon-related genes including MX1, IFI44L, XAF1 and IFIT1. However, only IL-17A directly downregulated keratinocyte differentiation-related and cornified envelope-related genes including FLG, LOR, C1ORF68, LCE1E, LCE1B, KRT10, CST6 and RPTN. In conclusion, IL-17A, a systemic inflammatory cytokine, affected keratinization in our 3-D epidermis model. In contrast, IL-17C, a locally produced cytokine, did not have strong effects on keratinization. Targeting IL-17A does not only reduce inflammation but it may also directly affect epidermal differentiation in psoriasis.

Increased expression of Psoriasin is correlated with poor prognosis of bladder transitional cell carcinoma by promoting invasion and proliferation.

Psoriasin, otherwise known as S100A7, is a member of the S100 protein family. With the key function of binding calcium, it is able to regulate a range of cellular functions. Altered Psoriasin expression is associated with poor clinical outcomes in several solid cancers. The present study aimed to examine the implication of Psoriasin in bladder cancer (BC). Expression of Psoriasin was examined in BC cell lines using PCR. Immunohistochemical (IHC) staining of Psoriasin was performed on a bladder disease spectrum tissue array. Plasmids were constructed to effectively knockdown and overexpress Psoriasin in BC cells and further utilized for in vitro BC cellular function assays. Association between Psoriasin expression and survival of patients with BC was evaluated using Kaplan­Meier survival analysis. Psoriasin was revealed to be expressed by both bladder epithelia and cancer cells as determined by IHC. Increased expression of Psoriasin was significantly correlated with a poor overall BC patient survival. Overexpression of Psoriasin in the EJ138 cell line increased cellular proliferation, adhesion and invasion, whereas knockdown exhibited the opposite effect on cellular functions in RT112 cells. Matrix metalloprotease (MMP)9 appeared to be the most affected of the three MMPs examined in these two BC cell lines. The analysis revealed a positive correlation in BC tumours between Psoriasin and MMP9. Overall, high Psoriasin expression was correlated with poor overall survival in BC patients and promoted invasiveness of BC cells via upregulation of MMPs. Psoriasin possesses certain prognostic and therapeutic potential in BC which requires further exploration.

Contribution of Immunohistochemistry in Revealing S100A7/JAB1 Colocalization in Psoriatic Epidermal Keratinocyte.

The application of immunohistological methods provides an invaluable contribution in revealing the protein colocalization, which may reflect the occurrence of molecular interaction processes.This chapter describes comprehensive protocols for detection of S100A7/JAB1 colocalization by immunohistochemistry in archival formalin-fixed and paraffin-embedded skin biopsies from healthy and psoriatic subjects. In addition, we provide a protocol for immunocytochemical detection of S100A7/JAB1 colocalization in S100A7 CRISPR-activated human keratinocyte cell line.

Downregulation of S100a7a antimicrobial peptide in acne vulgaris patients after isotretinoin therapy.

The S100a7a protein is expressed in keratinocytes, its level is increased in acne condition. As isotretinoin therapy is known to alter some of S100 peptides, these could be important specific targets for acne therapy and may have an important role in clinical remission. A randomized controlled trial was held in a dermatology clinic in Baghdad, where 30 patients with moderate to severe acne vulgaris condition aged 16-31 years were enrolled. Five milliliters of venous blood samples were taken before and after 6 weeks of isotretinoin therapeutic trial. A placebo-control group of 26 acne patients was also enrolled. The S100a7a peptide was measured in both groups using the ELISA technique before and after the trial. High levels of serum S100a7a were found in acne patients of both groups before therapeutic trial. Following the trial, a significant statistical difference (p = .0003) was noticed between mean S100a7a protein level of study and control groups. By comparing the mean S100a7a protein level before and after isotretinoin therapy in the study group, a highly significant statistical difference was also found (p = .001). The current study showed a downregulatory effect of isotretinoin therapy on the S100a7a peptide mean level.

The evolution of S100A7: an unusual gene expansion in Myotis bats.

BACKGROUND: The S100A7 gene, also called psoriasin, was first described as an upregulated protein in psoriatic skin. For the past years, the importance of this protein as a key effector of innate immunity has been clearly established, not only due to its importance protecting against bacteria skin insult in humans, but also because of its important role in amplifying inflammatory processes. Given the importance of S100A7 in host defense, S100A7 genes have been mostly studied in humans. Here we provide a detailed analysis of the evolution of the gene family encoding for the S100A7 protein in mammals. RESULTS: Examination of several mammalian genomes revealed an unexpected variation in the copy number of S100A7. Among the most representative mammalian groups, we report that multiple events of duplication, gene loss and high mutation rates are shaping the evolution of this gene family. An unexpected result comes from Myotis species (order Chiroptera), where we found an outstanding S100A7 gene radiation, resulting in more than 10 copies in M. lucifugus and 5 copies in M. brandtii. These findings suggest a unique adaptive road in these species and are suggestive of special role of this protein in their immune system. CONCLUSIONS: We found different evolutionary histories among different mammalian groups. Overall, our results suggest that this gene family is evolving under the birth-and-death model of evolution. To our knowledge, this work represents the first detailed analysis of phylogenetic relationships of S100A7 within mammals and therefore will pave the way to further clarify their unique function in the immune system.

Preparation of the Oxidized and Reduced Forms of Psoriasin (S100A7).

Human S100A7 (psoriasin) is a metal-chelating host-defense protein expressed by epithelial cells. S100A7 possesses two Cys residues that generate two redox isoforms of the protein. In the oxidized form (S100A7ox), Cys47 and Cys96 form an intramolecular disulfide bond, whereas these residues exist as free thiols in the reduced form (S100A7red). In this chapter, we provide a step-by-step protocol for the purification of S100A7ox and S100A7red that affords each protein in high yield and purity. In this procedure, S100A7 is expressed in Escherichia coli BL21(DE3), and the homodimer is obtained following ammonium sulfate precipitation, folding, and column chromatography. Treatment of S100A7 with 1,4-dithiothreitol (DTT) affords S100A7red. A Cu(II)-catalyzed oxidation reaction is employed to obtain S100A7ox. A RP-HPLC method that allows for baseline separation of S100A7ox and S100A7red is provided, as well as a biochemical Zn(II)-binding assay that can be employed to evaluate the functional integrity of S100A7.

S100A7 in Psoriasis: Immunodetection and Activation by CRISPR technology.

Psoriasis, an inflammatory autoimmune skin disease, is the result of a chronic interaction between hyperproliferative keratinocytes and infiltrating activated immune cells. The mechanisms underlying psoriasis pathogenesis remain largely unknown, although a combination of genetic and environmental factors plays an important role in its development. S100A7 is overexpressed in psoriasis, and there is growing evidence that S100A7 may be involved in the pathogenesis of psoriasis. Since the mechanisms underlying S100A7 regulation and function remain elusive, a better understanding of these mechanisms may be useful to uncover additional treatment approaches for psoriasis. Immunohistology provides invaluable tools for a better understanding of the pathogenetic mechanisms of psoriasis. Here, we describe basic methods for immunofluorescence and immunohistochemistry analysis of S100A7 expression in psoriatic patients as well as in S100A7 CRISPR-activated human keratinocyte cell line.

S100 Proteins as Biomarkers in Risk Estimations for Malignant Transformation in Oral Lesions.

Oncologic relevant members of S100 proteins are described as promising biomarkers in molecular pathology for risk estimation in oral neoplasia exhibiting different stages of malignancy: gingiva as healthy tissue, irritation fibroma as benign, leukoplakia as precancerous, and oral squamous cell carcinoma as malignant entity. Gene expression levels of S100A4 (metastasin), S100A7 (psoriasin), S100A8 (calgranulin A), and S100A9 (calgranulin B) were analyzed using quantitative RT-PCR. In addition, immunohistochemistry-based microscopy was used to examine cellular localization and distribution of these biomarkers in tissue sections. The results indicate that S100 proteins represent promising biomarkers for early-stage diagnosis in oral lesions. The inclusion of expression profiles and ratios for each entity even improves their diagnostic validity.

Mechanical stress induced S100A7 expression in human dental pulp cells to augment osteoclast differentiation.

OBJECTIVES: Mechanical injury of dental pulp leads to root resorption by osteoclasts/odontoclasts. S100 proteins have been demonstrated to be involved in inflammatory processes and bone remodeling. This study aimed to investigate the effect of mechanical stress on S100A7 expression by human dental pulp cells (HDPCs) and the effect of S100A7 proteins on osteoclast differentiation. MATERIALS AND METHODS: Isolated HDPCs were stimulated with compressive loading (2 and 6 hr), or shear loading (2, 6, and 16 hr). S100 mRNA expression and S100A7 protein levels were determined by real-time PCR and ELISA, respectively. Osteoclast differentiation was analyzed using primary human monocytes. The differentiation and activity of osteoclasts were examined by TRAcP staining and dentine resorption. In addition, the expression of S100A7 was analyzed in pulp tissues obtained from orthodontically treated teeth. RESULTS: Compressive and shear mechanical stress significantly upregulated both mRNA and protein level of S100A7. Dental pulp tissues from orthodontically treated teeth exhibited higher S100A7mRNA levels compared to non-treated control teeth. S100A7 promoted osteoclast differentiation by primary human monocytes. Moreover, S100A7 significantly enhanced dentine resorption by these cells. CONCLUSIONS: Mechanical stress induced expression of S100A7 by human dental pulp cells and this may promote root resorption by inducing osteoclast differentiation and activity.

Silver nanoparticles induce Egr-1-dependent psoriasin expression via the ERK and p38 pathways.

BACKGROUND: Silver nanoparticles (Ag-NPs) can prevent bacterial infection and improve cutaneous wound healing owing to their antimicrobial activity. However, the mechanism of their antimicrobial activity is poorly understood. AIM: To determine the mechanistic relationship between Ag-NP treatment and expression of psoriasin. METHODS: Human epidermal keratinocytes, neonatal (HEKn) were used. Psoriasin mRNA expression was measured by reverse transcription PCR and real-time PCR. Western blotting was performed to verify expression of early growth response-1 (Egr-1) and psoriasin, and phosphorylation of mitogen-activated protein kinase (MAPK). Psoriasin promoter activity by Egr-1 was detected by a luciferase assay. RESULTS: Treatment of HEKn with Ag-NPs induced psoriasin mRNA and protein expression. Upregulation of psoriasin promoter activity was also observed in the luciferase assay. Ag-NPs increased Egr-1 expression, promoter activity and nuclear translocation in HEKn. Psoriasin luciferase activity was increased in HEKn transfected with Egr-1 pcDNA 3.1. Ag-NPs activated MAPK pathways including the extracellular signal-regulated kinase (ERK), p38, and c-Jun-N-terminal kinase (JNK) pathways. The upregulation of Egr-1 expression by Ag-NP stimulation was inhibited by ERK and p38 inhibitors, but not by a JNK inhibitor. Psoriasin expression was reduced in Egr-1 small interfering RNA-transfected HEKn. CONCLUSIONS: Ag-NP treatment induces upregulation of psoriasin expression through Egr-1 expression. We suggest that the ERK and p38 pathways are involved in Egr-1-dependent psoriasin expression.