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PLoS One. 2014 Feb 28;9(2):e90284. doi: 10.1371/journal.pone.0090284. eCollection 2014.

IL-17 induces an expanded range of downstream genes in reconstituted human epidermis model.

Author information

1
Laboratory for Investigative Dermatology, The Rockefeller University, New York City, New York, United States of America ; Center for Clinical and Translational Science, The Rockefeller University, New York City, New York, United States of America ; Department of Dermatology, University of Rome "Tor Vergata", Rome, Italy.
2
Laboratory for Investigative Dermatology, The Rockefeller University, New York City, New York, United States of America ; Center for Clinical and Translational Science, The Rockefeller University, New York City, New York, United States of America.
3
Laboratory for Investigative Dermatology, The Rockefeller University, New York City, New York, United States of America.
4
Laboratory for Investigative Dermatology, The Rockefeller University, New York City, New York, United States of America ; Center for Clinical and Translational Science, The Rockefeller University, New York City, New York, United States of America ; Department of Dermatology, Mount Sinai School of Medicine, New York City, New York, United States of America.

Abstract

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.

PMID:
24587313
PMCID:
PMC3938679
DOI:
10.1371/journal.pone.0090284
[Indexed for MEDLINE]
Free PMC Article

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