Background: Anti-tumor necrosis factor alpha (TNF- α) therapy has made a significant impact on treating psoriasis. Despite these agents being designed to block TNF- α activity, their mechanism of action in the remission of psoriasis is still not fully understood at the molecular level.
Results: To better understand the molecular mechanisms of Anti-TNF- α therapy, we analysed the global gene expression profile (using mRNA microarray) in peripheral blood mononuclear cells (PBMCs) that were collected from 6 psoriasis patients before and 12 weeks after the treatment of etanercept. First, we identified 176 differentially expressed genes (DEGs) before and after treatment by using paired t-test. Then, we constructed the gene co-expression modules by weighted correlation network analysis (WGCNA), and 22 co-expression modules were found to be significantly correlated with treatment response. Of these 176 DEGs, 79 DEGs (M_DEGs) were the members of these 22 co-expression modules. Of the 287 GO functional processes and pathways that were enriched for these 79 M_DEGs, we identified 30 pathways whose overall gene expression activities were significantly correlated with treatment response. Of the original 176 DEGs, 19 (GO_DEGs) were found to be the members of these 30 pathways, whose expression profiles showed clear discrimination before and after treatment. As expected, of the biological processes and functionalities implicated by these 30 treatment response-related pathways, the inflammation and immune response was the top pathway in response to etanercept treatment, and some known TNF- α related pathways, such as molting cycle process, hair cycle process, skin epidermis development, regulation of hair follicle development, were implicated. Furthermore, additional novel pathways were also suggested, such as heparan sulfate proteoglycan metabolic process, vascular endothelial growth factor production, whose transcriptional regulation may mediate the response to etanercept treatment.
Conclusion: Through global gene expression analysis in PBMC of psoriasis patient and subsequent co-expression module based pathway analyses, we have identified a group of functionally coherent and differentially expressed genes (DEGs) and related pathways, which has not only provided new biological insight about the molecular mechanism of anti-TNF- α treatment, but also identified several genes whose expression profiles can be used as potential biomarkers for anti-TNF- α treatment response in psoriasis.
Keywords: Anti-tumor necrosis factor alpha (TNF- α) treatment; Etanercept; Peripheral blood mononuclear cells (PBMCs); Psoriasis.