Cell Kinetic Basis for Pathophysiology of Psoriasis

Weinstein, Gerald D.; McCullough, Jerry L.; Ross, Priscilla

doi:10.1111/1523-1747.ep12283594

Cited by 161 publications

(90 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The mean cell cycle duration of keratinocytes is reduced from 13 d to 36 h in psoriatic lesions (32). To test whether SFRP4 is capable of inhibiting keratinocyte hyperproliferation, we cultured NHEKs with 50 ng/ml rhIL-6 in the absence or presence of rhSFRP4.…”

Section: Sfrp4 Inhibits Keratinocyte Hyperproliferation In Vitromentioning

confidence: 99%

Epigenetic Downregulation of SFRP4 Contributes to Epidermal Hyperplasia in Psoriasis

Bai

Liu

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Psoriasis is a chronic recurrent inflammatory skin disorder characterized by the dysregulated cross-talk between epidermal keratinocytes and immune cells, leading to keratinocyte hyperproliferation. Several studies demonstrated that Wnt pathway genes were differentially expressed in psoriatic plaques and likely were involved in the pathophysiology of disease. However, the molecular mechanisms underlying Wnt signaling regulation in epidermal hyperplasia in psoriasis remain largely unknown. We report that the expression of secreted frizzled-related protein (SFRP) 4, a negative regulator of the Wnt signaling pathway, was diminished in lesional skin of mouse models and patients with psoriasis. SFRP4 directly inhibited excessive keratinocyte proliferation evoked by proinflammatory cytokines in vitro. Pharmacological inhibition of Wnt signaling or intradermal injection of SFRP4 decreased the severity of the psoriasiform skin phenotype in vivo, including decreased acanthosis and reduced leukocyte infiltration. Mechanistically, we identified that aberrant promoter methylation resulted in epigenetic downregulation of SFRP4 in inflamed skin of patients with psoriasis and in the IL-23–induced mouse model. Our findings suggest that this epigenetic event is critically involved in the pathogenesis of psoriasis, and the downregulation of SFRP4 by CpG island methylation is one possible mechanism contributing to the hyperplasia of epidermis in the disease.

show abstract

Section: Sfrp4 Inhibits Keratinocyte Hyperproliferation In Vitromentioning

confidence: 99%

Epigenetic Downregulation of SFRP4 Contributes to Epidermal Hyperplasia in Psoriasis

Bai

Liu

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Epidermal hyperplasia occurs when either the rate of individual cell proliferation or the growth fraction increases (2,3). It has been proposed that one way to control hyperplasia or neoplasia is to induce differentiation, thereby limiting or reducing the growth fraction (4)(5)(6).…”

mentioning

confidence: 99%

Methotrexate induces differentiation of human keratinocytes.

Schwartz

Barnett

Atillasoy

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Terminal differentiation is a key element in the maintenance of tissue homeostasis in the epidermis. We show here that methotrexate (MTX) induces differentiation of human epidermal keratinocytes in vitro. MTX inhibits proliferation of keratinocytes and also induces several markers of differentiation: a change in cell morphology, a marked increase in cell size, an increase in the proportion of cells that express involucrin, and an increase in the amount of cornifled envelope protein. These effects of MTX are dose-and exposure-timedependent and become irreversible after 24 hr, approximately one population doubling time. These effects of MTX cannot be attributed to cytotoxicity since keratinocytes not only remain viable but also actively synthesize proteins. MTX causes reproducible changes in the SDS/PAGE profiles of newly synthesized proteins and, in particular, increases the amount of involucrin synthesis. Thymidine completely prevents these effects of MTX, suggesting that they are caused by a depletion of thymine deoxyribonucleotides. The effect of MTX on keratinocytes may provide a model for studying the relationship between deoxyribonucleotide metabolism and differentiation in normal cells. In addition, the ability of MTX to induce differentiation in keratinocytes suggests a mechanism to explain its therapeutic action in psoriasis.

show abstract

“…As an example, we chose psoriasis that is characterized by hyperproliferation and abnormal differentiation of keratinocytes (Weinstein et al, 1985;Bernard et al, 1988;Kadunce and Krueger, 1995) and by overexpression of KGF (Finch et al, 1997). We analysed NM23-H1 and -H2 expression in normal human skin (NM23-H1: n ¼ 7, NM23-H2: n ¼ 3) and in skin of patients suffering from psoriasis (NM23-H1: n ¼ 8, NM23-H2: n ¼ 5).…”

Section: Nm23 Expression Is Upregulated In Psoriatic Skinmentioning

confidence: 99%

Novel roles of NM23 proteins in skin homeostasis, repair and disease

et al. 2006

View full text Add to dashboard Cite

Keratinocyte growth factor (KGF) is an important regulator of epidermal homeostasis and repair. Therefore, the identification of KGF target genes in keratinocytes should contribute to our understanding of the molecular mechanisms underlying these processes. In a search for KGF-regulated genes, we identified the gene encoding the nucleoside diphosphate kinase NM23-H1. Apart from a housekeeping function, NM23 proteins are involved in the regulation of many cellular processes as well as in tumor metastasis, but their functions in epidermal homeostasis and repair are largely unknown. Here, we show a high expression of NM23-H1 and NM23-H2 in the KGFresponsive keratinocytes of the hyperproliferative epidermis of mouse skin wounds and of patients suffering from the skin disease psoriasis. To determine if this overexpression is functionally important, we generated HaCaT keratinocyte cell lines overexpressing NM23-H1 and/or -H2. Whereas the enhanced levels of NM23 did not affect cell proliferation in monoculture, NM23-H2 and double transfectants but not NM23-H1 transfectants formed a strongly hyperthickened epithelium in threedimensional organotypic cultures. The abnormal epithelial morphology resulted from enhanced proliferation, reduced apoptosis and alterations in the differentiation pattern. These findings suggest that epidermal homeostasis depends on a tight regulation of the levels of NM23 isoforms.

show abstract

Cell Kinetic Basis for Pathophysiology of Psoriasis

Cited by 161 publications

References 15 publications

Epigenetic Downregulation of SFRP4 Contributes to Epidermal Hyperplasia in Psoriasis

Epigenetic Downregulation of SFRP4 Contributes to Epidermal Hyperplasia in Psoriasis

Methotrexate induces differentiation of human keratinocytes.

Novel roles of NM23 proteins in skin homeostasis, repair and disease

Contact Info

Product

Resources

About