A human endogenous retrovirus K dUTPase triggers a TH1, TH17 cytokine response: does it have a role in psoriasis?

Abstract

Psoriasis is a chronic inflammatory immune disease of the skin characterized by a complex interplay between multiple risk genes and their interactions with environmental factors. Recent haplotype analyses have suggested that deoxyuridine triphosphate nucleotidohydrolase (dUTPase) encoded by a human endogenous retrovirus K (HERV-K) may be a candidate gene for the psoriasis susceptibility 1 locus. However, no functional studies have been conducted to determine the role of HERV-K dUTPase in psoriasis. For this purpose, we constructed an HERV-K dUTPase wild-type sequence, as well as specific mutations reflecting the genotype characteristic of high- and low-risk haplotypes, purified the recombinant proteins, and evaluated whether they could modulate innate and/or adaptive immune responses. In this study, we demonstrate that wild-type and mutant HERV-K dUTPase proteins induce the activation of NF-κB through Toll-like receptor 2, independent of enzymatic activity. Proteome array studies revealed that treatment of human primary cells with wild-type and mutant HERV-K dUTPase proteins triggered the secretion of T(H)1 and T(H)17 cytokines involved in the formation of psoriatic plaques, including IL-12p40, IL-23, IL-17, tumor necrosis factor-α, IL-8, and CCL20, in dendritic/Langerhans-like cells and to a lesser extent in keratinocytes. These data support HERV-K dUTPase as a potential contributor to psoriasis pathophysiology.

• Authors: Maria-Eugenia Ariza, Marshall V Williams
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 131 Issue 12 Pg. 2419-27 (Dec 2011) ISSN: 1523-1747 [Electronic] United States
• PMID: 21776007 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• NF-kappa B
• TLR2 protein, human
• Toll-Like Receptor 2
• Viral Proteins
• Pyrophosphatases
• dUTP pyrophosphatase

Topics

• Cytokines (immunology, metabolism)
• Endogenous Retroviruses (enzymology, genetics)
• Haplotypes
• Humans
• Keratinocytes (immunology, metabolism, virology)
• Langerhans Cells (immunology, metabolism, virology)
• NF-kappa B (immunology, metabolism)
• Psoriasis (genetics, immunology, virology)
• Pyrophosphatases (genetics, immunology)
• Th1 Cells (immunology, metabolism, virology)
• Th17 Cells (immunology, metabolism, virology)
• Toll-Like Receptor 2 (immunology, metabolism)
• Viral Proteins (genetics, immunology)