Pathway Analysis of Skin from Psoriasis Patients after Adalimumab Treatment Reveals New Early Events in the Anti-Inflammatory Mechanism of Anti-TNF-α

Abstract

Psoriasis is a chronic cutaneous inflammatory disease. The immunopathogenesis is a complex interplay between T cells, dendritic cells and the epidermis in which T cells and dendritic cells maintain skin inflammation. Anti-tumour necrosis factor (anti-TNF)-α agents have been approved for therapeutic use across a range of inflammatory disorders including psoriasis, but the anti-inflammatory mechanisms of anti-TNF-α in lesional psoriatic skin are not fully understood. We investigated early events in skin from psoriasis patients after treatment with anti-TNF-α antibodies by use of bioinformatics tools. We used the Human Gene 1.0 ST Array to analyse gene expression in punch biopsies taken from psoriatic patients before and also 4 and 14 days after initiation of treatment with the anti-TNF-α agent adalimumab. The gene expression was analysed by gene set enrichment analysis using the Functional Annotation Tool from DAVID Bioinformatics Resources. The most enriched pathway was visualised by the Pathview Package on Kyoto Encyclopedia of Genes and Genomes (KEGG) graphs. The analysis revealed new very early events in psoriasis after adalimumab treatment. Some of these events have been described after longer periods of anti-TNF-α treatment when clinical and histological changes appear, suggesting that effects of anti-TNF-α treatment on gene expression appear very early before clinical and histological changes. Combining microarray data on biopsies from psoriasis patients with pathway analysis allowed us to integrate in vitro findings into the identification of mechanisms that may be important in vivo. Furthermore, these results may reflect primary effect of anti-TNF-α treatment in contrast to studies of gene expression changes following clinical and histological changes, which may reflect secondary changes correlated to the healing of the skin.

RNA-seq and flow-cytometry of conventional, scalp, and palmoplantar psoriasis reveal shared and distinct molecular pathways

“…3). Top up-regulated genes include SFRP4 , which was interestingly found to be down-regulated in psoriasis skin 16 , and CCL13 , which was also found to be down-regulated in lesional psoriasis skin 17 .…”

Targeting genes and signaling pathways of transcriptional suppressor ZHX2 in hepatocellular carcinoma: a Chromatin Immunoprecipitation-sequencing (ChIP-seq) investigation

“…The Gene Ontology database (gene ontology, GO) (http://www.geneontology.org/) was used for the classification and functional analysis of genes with ZHX2 binding sites [17][18][19][20][21][22]. Genes with ZHX2 binding sites were used for pathway enrichment analyses based on the Kyoto Encyclopedia of Genes and Genomes (KEGG, http://www.genome.jp) [20,[23][24][25][26][27][28][29]. A p<0.05 was set as the threshold value of significant gene enrichment.…”

Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

“…In addition to the classical view on TNF signaling in inducing immediate genes (e.g., IL1, IL6, and IL8), this points to its role in orchestrating multicellular responses by involving the adaptive immune system through for example IFNγ. In the case of adalimumab treatment of psoriasis patients, these changes could be observed gradually in the molecular profile and as early as from day four on [229,230], although TNF inhibitors are known to show a latency in lesion resolution.…”