Regulatory Networks Contributing to Psoriasis Susceptibility

Abstract

The non-involved, healthy-looking skin of psoriatic patients displays inherent characteristics that make it prone to develop typical psoriatic symptoms. Our primary aim was to identify genes and proteins that are differentially regulated in the non-involved psoriatic and the normal epidermis, and to discover regulatory networks responsible for these differences. A cDNA microarray experiment was performed to compare the gene expression profiles of 4 healthy and 4 psoriatic non-involved epidermis samples in response to T-cell lymphokine induction in organotypic cultures. We identified 61 annotated genes and another 11 expressed transcripts that were differentially regulated in the psoriatic tissues. Bioinformatics analysis suggested that the regulation of cell morphology, development and cell death is abnormal, and that the metabolism of small molecules and lipids is differentially regulated in psoriatic epidermis. Our results indicate that one of the early steps of psoriasis pathogenesis may be the abnormal regulation of IL-23A and IL-1B genes in psoriatic keratinocytes.

Characterization of molecules showing altered expression profile in psoriasis

“…CARD18 has been identified as a negative regulator of inflammasome activation through direct interaction with the CARD domain of pro-caspase-1 and abrogation of IL-1␤ and Il-18 production in macrophages (Humke et al, 2000). We have identified CARD18 as a highly expressed transcript in psoriatic noninvolved epidermis and demonstrated its abnormal regulation in psoriatic non-involved epidermis (Szabó et al, 2014). To understand the pathologic functions of CARD18 in skin inflammation, we studied CARD18 under normal and inflammatory conditions both in vitro and in vivo.…”

“…However, the level of induction was different: modest elevation was detected in psoriatic non-involved epidermis compared to healthy and psoriatic involved epidermis. The higher basal level and the lack of response of CARD18 gene and protein expression in psoriatic non-involved epidermis might indicate a "ceiling effect" or impaired regulation of inflammatory signaling, similar to the phenomenon that has been described for IL-1␤ production in keratinocytes and in salivary glands Szabó et al, 2014).…”

“…We have recently reported the results of a cDNA microarray experiments in which 61 annotated genes were differentially expressed in psoriatic non-involved and healthy epidermis upon T-cell lymphokine treatment (Szabó et al, 2014). In this experiment, organotypic skin cultures were treated with a cytokine mixture (GM-CSF, IL-3, IFN-γ) that has been shown to mimic the effect of psoriatic T-cell lymphokines (Bata-Csorgo et al, 1995).…”

“…Subsequently, organotypic skin cultures were established, as has been described previously (Szabó et al, 2014).…”

“…Our recent large-scale gene expression study has revealed that the caspase recruitment domain family member 18 (CARD18, Iceberg) transcript is differentially expressed in psoriatic noninvolved epidermis compared to healthy epidermis (Szabó et al, 2014). CARD18, a member of CARD-only protein (COP) family, has only one CARD domain which exhibits sequence similarity to the CARD prodomain of caspase-1.…”