title: 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.affiliation: Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina, USA. maria.ariza@osumc.edu
authors.forename: Maria-Eugenia
authors.initials: ME
authors.lastname: Ariza
authors.forename: Marshall V
authors.initials: MV
authors.lastname: Williams
mesh_terms: D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D020077:Endogenous Retroviruses / Q000201:enzymology* / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D007801:Langerhans Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D011565:Psoriasis / Q000235:genetics / Q000276:immunology / Q000821:virology*; D011755:Pyrophosphatases / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014764:Viral Proteins; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase