IL-17 Induces an Expanded Range of Downstream Genes in Reconstituted Human Epidermis ModelReport as inadecuate




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Background

IL-17 is the defining cytokine of the Th17, Tc17, and γδ T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines with relevant contributions of IFN-γ, TNF-α, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro.

Methodology-Principal Findings

Given the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. Using a reconstructed human epidermis RHE, IL-17 was able to upregulate 419 gene probes and downregulate 216 gene probes. As possible explanation for the increased gene induction in the RHE model is that C-CAAT-enhancer-binding proteins C-EBP -β, the transcription factor regulating IL-17-responsive genes, is expressed preferentially in differentiated keratinocytes.

Conclusions-Significance

The genes identified in IL-17-treated RHE are likely relevant to the IL-17 effects in psoriasis, since ixekizumab anti-IL-17A agent strongly suppressed the -RHE- genes in psoriasis patients treated in vivo with this IL-17 antagonist.



Author: Andrea Chiricozzi , Kristine E. Nograles, Leanne M. Johnson-Huang, Judilyn Fuentes-Duculan, Irma Cardinale, Kathleen M. Bonifacio

Source: http://plos.srce.hr/



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