Keratinocyte Proliferation In Psoriasis Research Articles

A Comparative Study on Serum Levels of “Thymic Stromal Lymphopoietin” Between Patients with Psoriasis Vulgaris and Healthy Individuals: A Case-Control Study

Abstract Background: Thymic stromal lymphopoietin (TSLP) is a cytokine initially implicated to be associated with allergic disorders inducing Th2 response. Emerging studies have shown that TSLP is also involved in autoimmune diseases. In psoriasis, TSLP acts in synergy with T cell-derived CD40L to promote the release of IL-23 from dendritic cells. IL-23 is responsible for the inappropriate immune reaction and keratinocyte proliferation in psoriasis. Targeting TSLP could be a novel therapeutic approach in the treatment of psoriasis. Objective: To compare the serum levels of TSLP between patients with psoriasis and healthy individuals. Materials and Methods: A prospective hospital-based case-control study was carried out on 38 patients with psoriasis. The severity of psoriasis was graded into mild, moderate, and severe according to PASI. A total of 30 healthy individuals with matched age and sex were taken as controls. 5 ml of venous blood was collected, centrifuged, and the collected serum was stored at -80°C until quantitative assessment by sandwich enzyme-linked immunosorbent assay (ELISA) technique. Results: TSLP has been found to be significantly elevated in the sera of cases (0.1380178 pg/ml) than in controls (0.1125974 pg/ml). There was also a significant proportionate increase in the mean TSLP with the mean PASI score. Limitations: The sample size was small and we could not follow-up the cases to study the changes in TSLP levels with remission of the lesions. Conclusion: We found that serum TSLP was elevated in psoriasis patients and correlated with disease severity, indicating a possible pathogenetic role.

Neutrophil-Derived MicroRNA-1290 Promotes Keratinocyte Proliferation in Psoriasis

The pathological hallmark of psoriasis is the infiltration of neutrophils into the skin. Some neutrophil-derived microRNAs (miRNAs) serve as biomarkers for various diseases, but none have been reported for psoriasis. In this study, we investigated the involvement of miRNAs released from neutrophils in psoriasis pathogenesis. We compared the expression of miRNAs in the sera of patients with psoriasis with that in healthy individuals and found that the expression of 2 miRNAs-miR-223 and miR-1290-was significantly upregulated in the sera of patients with psoriasis. The serum levels of these miRNAs positively correlated with the PASI and CRP levels. We used all-trans retinoic acid to induce the differentiation of human promyelocytic leukemia HL-60 cells into neutrophil-like cells and found that the release of both miRNAs increased during differentiation. Furthermore, the release of miR-1290 was increased by TNF-α in neutrophil-like cells and human neutrophils. Treatment with the miR-1290 precursor promoted the proliferation of human keratinocytes, increased the proportion of S-phase cells, and upregulated the phosphorylation of extracellular signal-regulated kinase 1/2. These results suggest that miR-1290 plays a vital role in regulating neutrophil differentiation and keratinocyte proliferation and could be a serum marker of psoriasis severity.

SLC35E1 promotes keratinocyte proliferation in psoriasis by regulating zinc homeostasis

Keratinocyte hyperproliferation is a key pathogenic factor in psoriasis. However, the mechanisms that regulate keratinocyte hyperproliferation in this condition remain unclear. Here, we found that SLC35E1 was highly expressed in keratinocytes of patients with psoriasis and that Slc35e1−/− mice displayed a less severe imiquimod (IMQ)-induced psoriasis-like phenotype than their wild-type siblings. In addition, SLC35E1 deficiency inhibited keratinocyte proliferation in both mice and cultured cells. On a molecular level, SLC35E1 was found to regulate zinc ion concentrations and subcellular localization, while zinc ion chelation reversed the IMQ-induced psoriatic phenotype in Slc35e1−/− mice. Meanwhile, epidermal zinc ion levels were decreased in patients with psoriasis and zinc ion supplementation alleviated the psoriatic phenotype in an IMQ-induced mouse model of psoriasis. Our results indicated that SLC35E1 can promote keratinocyte proliferation by regulating zinc ion homeostasis and zinc ion supplementation has potential as a therapy for psoriasis.

Keratin 17 covalently binds to alpha-enolase and exacerbates proliferation of keratinocytes in psoriasis.

Dysregulated glucose metabolism is an important characteristic of psoriasis. Cytoskeletal protein keratin 17 (K17) is highly expressed in the psoriatic epidermis and contributes to psoriasis pathogenesis. However, whether K17 is involved in the dysregulated glucose metabolism of keratinocytes (KCs) in psoriasis remains unclear. In the present study, loss- and gain-of-function studies showed that elevated K17 expression was critically involved in glycolytic pathway activation in psoriatic KCs. The level of α-enolase (ENO1), a novel potent interaction partner of K17, was also elevated in psoriatic KCs. Knockdown of ENO1 by siRNA or inhibition of ENO1 activity by the inhibitor ENOBlock remarkably suppressed KCs glycolysis and proliferation. Moreover, ENO1 directly interacted with K17 and maintained K17-Ser44 phosphorylation to promote the nuclear translocation of K17, which promoted the transcription of the key glycolysis enzyme lactic dehydrogenase A (LDHA) and resulted in enhanced KCs glycolysis and proliferation in vitro. Finally, either inhibiting the expression and activation of ENO1 or repressing K17-Ser44 phosphorylation significantly alleviated the IMQ-induced psoriasis-like phenotype in vivo. These findings provide new insights into the metabolic profile of psoriatic KCs and suggest that modulation of the ENO1-K17-LDHA axis is a potentially innovative therapeutic approach to psoriasis.

IL-17A Promotes Psoriasis-Associated Keratinocyte Proliferation through ACT1-Dependent Activation of YAP–AREG Axis

Psoriasis is a recurrent inflammatory skin disorder characterized by epidermal hyperplasia, which is primarily driven by IL-17A. The Hippo-YAP signaling pathway plays a vital role in cell survival and tissue growth, and its target gene, AREG, has been reported to promote the development of psoriasis. However, whether IL-17A promotes keratinocyte proliferation through regulating Hippo-YAP signaling has not been explored. In this study, we show that the YAP-AREG pathway is activated in human psoriatic skin and is suppressed by IL-17A antagonist secukinumab and that imiquimod and IL-17A administration activates the YAP-AREG axis in mice epidermis. Invitro studies using HaCaT and normal human epidermal keratinocyte cells suggest that IL-17A enhances AREG expression and keratinocyte proliferation by activating Hippo-YAP signaling. Mechanistically, IL-17A stimulates the recruitment of MST1 to ACT1 in keratinocytes, which leads to reduced MST1-LATS1 interaction and YAP dephosphorylation. Together, our findings reveal a previously unknown mechanism in which IL-17A promotes keratinocyte proliferation in psoriasis, namely through activating YAP-AREG signaling.

Lysophosphatidic Acid Mediates Imiquimod-Induced Psoriasis-like Symptoms by Promoting Keratinocyte Proliferation through LPAR1/ROCK2/PI3K/AKT Signaling Pathway

Psoriasis is a chronic inflammatory skin disease. Recently, lysophosphatidic acid (LPA)/LPAR5 signaling has been reported to be involved in both NLRP3 inflammasome activation in macrophages and keratinocyte activation to produce inflammatory cytokines, contributing to psoriasis pathogenesis. However, the effect and molecular mechanisms of LPA/LPAR signaling in keratinocyte proliferation in psoriasis remain unclear. In this study, we investigated the effects of LPAR1/3 inhibition on imiquimod (IMQ)-induced psoriasis-like mice. Treatment with the LPAR1/3 antagonist, ki16425, alleviated skin symptoms in IMQ-induced psoriasis-like mouse models and decreased keratinocyte proliferation in the lesion. It also decreased LPA-induced cell proliferation and cell cycle progression via increased cyclin A2, cyclin D1, cyclin-dependent kinase (CDK)2, and CDK4 expression and decreased p27Kip1 expression in HaCaT cells. LPAR1 knockdown in HaCaT cells reduced LPA-induced proliferation, suppressed cyclin A2 and CDK2 expression, and restored p27Kip1 expression. LPA increased Rho-associated protein kinase 2 (ROCK2) expression and PI3K/AKT activation; moreover, the pharmacological inhibition of ROCK2 and PI3K/AKT signaling suppressed LPA-induced cell cycle progression. In conclusion, we demonstrated that LPAR1/3 antagonist alleviates IMQ-induced psoriasis-like symptoms in mice, and in particular, LPAR1 signaling is involved in cell cycle progression via ROCK2/PI3K/AKT pathways in keratinocytes.

Beclin1 in psoriasis: an immunohistochemical study.

Abnormal autophagy is known to be associated with the pathogenesis of some skin disorders. The protein Beclin1 plays a central role in the machinery of autophagy. To assess the expression of Beclin1 in psoriasis, using immunohistochemical study in lesional and perilesional skin in patients with psoriasis, and to compare the results with those of an apparently healthy control (HC) group. This case-control study enrolled a total of 40 participants: 20 patients with chronic plaque psoriasis and 20 age- and sex-matched, apparently HCs. Skin biopsies were taken from (i) lesional and (ii) perilesional skin of patients with psoriasis and from (iii) normal skin of HCs for immunohistochemical evaluation of Beclin1 expression. Epidermal Beclin1 expression was positive in all three studied groups. There was a significant difference between the three studied groups regarding Beclin1 epidermal topographic distribution, epidermal staining intensity, H score and H-score category (P<0.01 for all). Significant differences were found between the three studied groups regarding Beclin1 H score and H-score category for skin adnexal structures (P<0.01 for both). For dermal inflammatory infiltrate, significant differences were found between lesional and perilesional skin regarding Beclin1 expression status, staining intensity, H score and H-score category (P<0.01, P=0.01, P<0.01 and P<0.03, respectively). The increased expression of Beclin1 in psoriatic skin, both lesional and perilesional, reflects increased autophagy, which could be a consequence of the rapid keratinocyte proliferation in psoriasis, which would also ramp up all the cellular processes including autophagy. The cellular localization of Beclin1 was nucleocytoplasmic in psoriasis skin but cytoplasmic only in normal HC skin, which needs further study to allow its interpretation.

MiR-146b correlates with increased disease activity and psoriatic tissue inflammation and promotes keratinocyte proliferation in psoriasis.

The present study aimed to investigate the expression of microRNA (miR)-146b in psoriatic tissue and its correlation with psoriasis activity and inflammation. The effect of miR-146b overexpression on keratinocyte proliferation and apoptosis was also explored. The expression of miR-146b in the psoriasis-affected tissue and non-affected tissue of 110 patients was determined via reverse transcription-quantitative (RT-q)PCR. The psoriasis-affected body surface area and psoriasis area severity index (PASI) score were recorded for evaluating disease activity. The expression of various inflammatory cytokines in psoriasis-affected tissue was also detected via RT-qPCR. miR-146b overexpression and control plasmids were constructed and transfected into HaCaT cells in vitro. Subsequently, cell proliferation, apoptosis and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced cell apoptosis were determined. The results revealed that the expression of miR-146b was increased in psoriasis-affected tissue compared with that in unaffected tissue. The results obtained from a receiver operating characteristic curve analysis demonstrated that miR-146b levels were able to discriminate between psoriasis-affected tissue and unaffected tissue, with an area under the curve value of 0.781 (95% CI: 0.720-0.843). In addition, miR-146b expression in psoriatic tissue was correlated with an increased PASI score in patients with psoriasis. miR-146b expression in psoriatic tissue was positively correlated with TNF-α, interleukin (IL)-6 and IL-17 mRNA levels. In vitro, miR-146b overexpression enhanced HaCaT cell proliferation and suppressed apoptosis as well as TRAIL-induced apoptosis when compared with that in control-transfected HaCaT cells. In conclusion, miR-146b was positively correlated with disease activity and psoriatic tissue inflammation. Keratinocyte proliferation was also promoted in psoriasis.

Pathological role of excessive DNA as a trigger of keratinocyte proliferation in psoriasis.

Psoriasis is characterized by excessive growth and aberrant differentiation of epidermal keratinocytes due to persistent inflammation. However, the underlying mechanism that triggers immune activation in psoriasis is not clear. In this study, we explored excessive DNA as a potential trigger of psoriasis using cultured human keratinocytes and psoriatic skin tissues. We demonstrated that human genomic DNA fragments induced tumour necrosis factor (TNF)-α expression, hyperproliferation and over-expression of heparin-binding epidermal-like growth factor (HB-EGF) and transforming growth factor (TGF)-α, accompanied by defective expression of keratins 1 and 10 in cultured normal human epidermal keratinocytes, which have a similar phenotype to that of keratinocytes in psoriatic skin lesions. In psoriatic lesions, we found high levels of double-stranded (ds)DNA fragments, accompanying keratinocytes expressing Ki-67, HB-EGF and TNF-α. In addition, we showed that 1,25-dihydroxyvitamin D3 inhibited genomic DNA fragment-induced TNFA and interleukin-1β (IFNB) expression in human keratinocytes, and an intact function of cathelicidin anti-microbial peptide (CAMP) was required for this effect. These results suggest that excessive dsDNA fragments probably act as a risk factor for immune activation in psoriasis, and the active form of vitamin D can prevent genomic DNA-mediated skin inflammation via CAMP.

Role of SPRED1 in keratinocyte proliferation in psoriasis.

Psoriasis is a recurrent inflammatory skin disease, affecting approximately 2% of the population. Previous studies have demonstrated that psoriatic dermal mesenchymal stem cells (DMSC) stimulated keratinocyte (KC) proliferation and that psoriasis exhibited missense SPRED1 mutations. To further investigate the molecular mechanism by which psoriatic DMSC stimulate KC proliferation, and the role of missense SPRED1 mutations in psoriasis, we assessed expression levels of miRNA, and both mRNA and protein of SPRED1 in normal human epidermal keratinocyte cells (NHEK) cocultured with either psoriatic or control DMSC. Expression levels of miRNA and mRNA were determined by RNA sequencing. Expression levels of spred1 protein were assessed using western blot analysis. Moreover, the variation in SPRED1 was also examined by whole-genome sequencing in 665 psoriatic patients, and verified by Sanger sequencing. Our results showed that coculture of NHEK with psoriatic DMSC induced 32 differentially expressed miRNA, in which expression levels of miR-1 increased approximately 16-fold over control DMSC-treated NHEK (P<0.05). Likewise, expression levels of miR-21-3p increased over twofold (P<0.05). Moreover, coculture of NHEK with psoriatic DMSC induced marked increase in expression levels of mRNA for MAPK3, CDC25B and CDC25C, while decreasing expression levels of SPRED1 mRNA and protein in comparison with control DMSC treatment (P<0.05 for all between cocultured with control and psoriatic DMSC). Furthermore, psoriasis displayed non-synonymous mutation of SPRED1 enriched in exon 7: c.A881T:p.Y294F (chr15:38351210). These results suggest that dysregulation and mutations of SPRED1 may participate in the pathogenesis of psoriasis, including epidermal hyperproliferation.

Loss of expression of claudin-1 in psoriasis is associated with proliferative state of keratinocytes

Background: Psoriasis is a chronic remitting and relapsing inflammatory disease, with a prevalence of 0.44%–2.5% and is characterized by T-cell-mediated rapid turnover of epithelial cells. Claudin-1 protein is an integral part of the keratinocyte tight junction and has a role in proliferation, differentiation, and cell adhesion. Aim: The aim of the study was to investigate the role of claudin-1 expression in relation to keratinocyte proliferation in psoriasis. Materials and Methods: Fifty cases of psoriasis were included in the study. Skin biopsies were subjected to claudin-1 and Ki67 immunohistochemistry. Claudin-1 expression in the basal and spinous layers was scored. Ki67 proliferation index was assessed. Seven cases of normal skin biopsies were also included as controls. Fisher's exact test was applied for statistical analysis. Results: The cases had a wide age range (14–78 years), with a mean of 46 years with a male preponderance (4:1). The basal cell layer showed a complete loss of expression for claudin-1 in 82% (n = 42). The spinous layer showed a decrescendo pattern of loss of claudin-1 expression in 96% (n = 48). The association of loss of expression of claudin-1 between the basal layer and spinous layer was statistically significant (P = 0.0229). The association of loss of expression of claudin-1 and high Ki67 proliferative index was also statistically significant (P

FGF19 sustains the high proliferative ability of keratinocytes in psoriasis through the regulation of Wnt/GSK-3β/β-catenin signalling via FGFR4.

Accumulating evidence has shown that fibroblast growth factor 19 (FGF19) plays an important role in regulating cell proliferation. Psoriasis is characterized by the hyperproliferation of keratinocytes in skin lesions. However, whether FGF19 regulates the proliferation of keratinocytes in psoriasis remains unknown. In this study, we aimed to explore the potential relevance of FGF19 in psoriasis. We found that FGF19 was highly expressed in psoriatic skin from psoriasis patients, as well as keratinocytes that were stimulated with a cocktail of cytokines (M5), which is an in vitro model of psoriasis. Functional experiments demonstrated that FGF19 overexpression promoted the growth and proliferation of keratinocytes, while FGF19 knockdown showed opposite effect. Moreover, we found that FGF19 increased the phosphorylation of glycogen synthase kinase (GSK)-3β and promoted the expression of β-catenin and the activation of T cell factor 4 (TCF4) transcriptional activity. Notably, blocking Wnt/β-catenin signalling by silencing β-catenin partially reversed FGF19-mediated promotional effects on keratinocyte proliferation. In addition, FGFR4 inhibition significantly blocked the promotional effect of FGF19 on keratinocyte proliferation and GSK-3β/β-catenin/TCF4 signalling. Taken together, our results demonstrated that FGF19 contributes to sustaining the high proliferative ability of keratinocytes through promoting Wnt/GSK-3β/β-catenin signalling via FGFR4, highlighting the importance of FGF19 in the pathogenesis of psoriasis. Our study suggests that FGF19 may serve as a novel and potential therapeutic target for psoriasis.

Smad7 positively regulates keratinocyte proliferation in psoriasis.

Transforming growth factor (TGF)-β1 exerts inhibitory effects on keratinocyte proliferation. To examine whether Smad7, a known inhibitor of TGF-β1 signalling, is involved in psoriasis-associated keratinocyte hyperproliferation. Smad7 was evaluated in skin sections of patients with psoriasis and healthy controls and in mice with Aldara-induced skin pathology by real-time polymerase chain reaction and immunohistochemistry. To assess whether Smad7 positively regulates in vivo keratinocyte growth, mice treated with Aldara received daily cutaneous administration of Smad7 antisense oligonucleotide (AS). Keratin (K)6 and K16, cell-cycle-associated factors, cell-cycle and cell proliferation were evaluated in HaCaT cells either treated with Smad7 AS or transfected with Smad7 plasmid and in mice given Smad7 AS. Smad7 was highly expressed in keratinocytes of patients with psoriasis and of mice treated with Aldara. In HaCaT cells, Smad7 knockdown inhibited cell growth, reduced K6 and K16 expression and promoted accumulation of cells in the S-phase of the cell cycle. Smad7-deficient keratinocytes exhibited reduced levels of CDC25A protein, a phosphatase that facilitates progression of cells through the S-phase, and hyperphosphorylation of eukaryotic initiation factor 2 (eIF2)α, a negative regulator of CDC25 protein translation. Consistently, Smad7 overexpression in HaCaT cells was followed by induction of K6 and K16 and increased cell proliferation. Topical application of Smad7 AS to Aldara-treated mice reduced epidermal thickness. Our data show that Smad7 is overexpressed in human and murine psoriasis and suggest a key role of this molecule in the control of keratinocyte proliferation.

Nrf2 Promotes Keratinocyte Proliferation in Psoriasis through Up-Regulation of Keratin 6, Keratin 16, and Keratin 17

Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation of epidermis. Although hyperproliferation-associated keratins K6, K16, and K17 are considered to be the hallmarks of psoriasis, the molecular basis underlying the overexpression of these keratins remains unclear. Nrf2 regulates cell proliferation. Therefore, we investigated whether Nrf2 regulates keratinocyte proliferation via promoting expression of K6, K16, and K17 in psoriasis. We initially found that psoriatic epidermis exhibited elevated expression of Nrf2. Furthermore, Nrf2 promoted expression of K6, K16, and K17 in both HaCaT cells and primary human keratinocytes by binding to the ARE domains located in the promoter of these genes. Additionally, upon stimulation with IL-17 or IL-22, Nrf2 translocated to the nucleus and initiated expression of targeted keratins. In mice of imiquimod-induced psoriasis-like dermatitis, topical application of Nrf2 small interfering RNA alleviated the epidermal hyperplasia with reduced expression of these keratins. More importantly, Nrf2 promoted the proliferation of human keratinocytes through up-regulation of K6, K16, or K17. These data suggested that inflammatory cytokines promoted Nrf2 nuclear translocation in psoriatic epidermis, which led to elevated expression of K6, K16, and K17, thus promoting keratinocyte proliferation and contributing to the pathogenesis of psoriasis.

465 Role of cortical actin disorganization in keratinocyte proliferation in psoriasis

465 Role of cortical actin disorganization in keratinocyte proliferation in psoriasis

441 Role of galectin-8 in keratinocyte proliferation in psoriasis

441 Role of galectin-8 in keratinocyte proliferation in psoriasis

Cytotoxic T lymphocytes as a potential brake of keratinocyte proliferation in psoriasis

Psoriasis is a chronic papulosquamous skin disease, histologically characterized by epidermal hyperproliferation and dermal infiltration of inflammatory cells. The majority of T lymphocytes infiltrating dermis are CD4+ T lymphocytes secreting type 1 and type 17 cytokines. These cytokines are responsible for triggering keratinocyte proliferation as well as chemokine secretion and subsequent migration of other inflammatory cells in the skin. Contrarily, lymphocytes that accumulate in epidermis are mainly CD8+ T lymphocytes. According to the recent findings, these cells can also secrete type 1 and type 17 cytokines. However, it is demonstrated so far that epidermal CD8+ T lymphocytes contain higher amounts of cytolytic molecules, such as perforin, granzyme B and granulysin whose role in psoriasis pathogenesis is still unknown. Therefore, in this article we hypothesize the active involvement of cell mediated cytotoxicity in killing the proliferating keratinocytes as a mechanism of potential self-defense and possible brake in psoriatic plaque formation, maintaining skin homeostasis.

Peptidoglycan from Staphylococcus aureus has an anti‐apoptotic effect in HaCaT keratinocytes mediated by the production of the cellular inhibitor of apoptosis protein‐2

Colonization of epithelium by microorganisms leads to inflammatory responses. In some cases an anti-apoptotic response involving the cellular inhibitor of apoptosis protein-2 (cIAP-2) also occurs. Although strong expression of cIAP-2 has been observed in lesional skin from psoriatic patients and in HaCaT keratinocytes treated with peptidoglycan (PGN) from Staphylococcus aureus, anti-apoptotic responses induced in the skin by cIAP-2 have seldom been studied. In this study, the effect of PGN on TNF-α-induced apoptotic HaCaT keratinocytes was assessed. Morphological analysis, quantification of cells with DNA fragmentation and active caspase-3 detection was performed to assess apoptotic cell death. Greater LL-37 and cIAP-2 production was found in keratinocytes stimulated with PGN than in non-treated cells (P < 0.05). In comparison with cells treated with TNF-α only, a significant reduction in apoptotic cell death was observed when HaCaT were pretreated with PGN before inducing apoptosis with TNF-α (P < 0.05). In addition, an inhibitor of cIAP-2 activity (LCL161) stopped the PGN effect. These findings show that PGN from S. aureus has an anti-apoptotic effect in keratinocytes mediated by cIAP-2 production, suggesting that this anti-apoptotic activity could favor proliferation of keratinocytes in psoriasis.

Immunohistochemical Expression of GLUT-1 and Ki-67 in Chronic Plaque Psoriasis

Many inflammatory mediators and other biological markers are upregulated in psoriatic lesions; some of these alterations also persist in nonlesional skin. Glucose is the major source of energy for cells, and glucose transporter 1 is the most common glucose transporter in humans (GLUT-1). The present study aimed at evaluating the pattern of expression of GLUT-1 and Ki-67 in psoriatic skin (involved and uninvolved) and correlating their expression with the clinicopathological parameters in the studied patients. This study was carried out on 30 patients presented with chronic plaque psoriasis and 10 apparently healthy volunteers as a control group. GLUT-1 was not expressed in epidermis of normal skin, whereas it was expressed in 76.6% of uninvolved and 86.7% of involved skin of psoriatic patients, where both the latter differed significantly regarding the intensity (P = 0.001) and localization (P = 0.001) of GLUT-1 expression. The percentage of Ki-67 expression did not differ significantly between involved and uninvolved skin of psoriatic patients, but they were higher than that of normal skin of control group. Nucleolar pattern of Ki-67 expression was significantly associated with male sex (P = 0.05), marked parakeratosis (P = 0.01), and marked angiogenesis (P = 0.05). GLUT-1 expression was associated with degree of acanthosis and percentage of Ki-67 expression. From this study, GLUT-1 is upregulated in psoriatic epidermis and may be involved in facilitation of keratinocyte proliferation in psoriasis. Nucleolar pattern of Ki-67 is an indicator of progressive keratinocyte proliferation in psoriasis.

Interleukin (IL)-19 promoted skin wound healing by increasing fibroblast keratinocyte growth factor expression

BackgroundInterleukin (IL)-19, a member of the IL-10 cytokine family, is involved in keratinocyte proliferation in psoriasis. ObjectivesWe investigated the role of IL-19 in the wound-healing process in vivo and in vitro. MethodsTwo full-thickness circular wounds (4mm in diameter) were punched into the skin of BALB/C mice. IL-19 and keratinocyte growth factor (KGF) mRNA in wounded skin were determined using real-time PCR. The wounds were treated with PBS, vehicle, IL-19 (400ng/mL), or IL-20 (400ng/mL) (n=6 in each group) twice daily and the percentage of wound healing was measured daily for 7days. In vitro, human skin fibroblast CCD966-SK cells and keratinocyte HaCaT cells were treated with IL-19 or KGF. Cell proliferation and migration were determined using bromodeoxyuridine (BrdU) and transwell assays, respectively. The expression of IL-19 and KGF mRNA was also analyzed. ResultsIn wounded mouse skin, IL-19 mRNA was upregulated at 12h, and KGF at 24h after the injury. Both increases in gene expression declined 72h after the skin had been wounded. The percentage of wound healing in IL-19-treated mice was higher than in control mice. In vitro, IL-19 upregulated KGF expression in the CCD966-SK cells; IL-19 was upregulated in KGF-treated HaCaT cells. KGF but not IL-19 promoted HaCaT cell proliferation. However, IL-19 significantly increased the migration of HaCaT cells. HaCaT cells treated with the cultured supernatants of IL-19-stimulated CCD966-SK cells showed significantly more proliferation than in controls. ConclusionsIL-19 is important for cutaneous wound healing because it upregulates KGF expression.