The development and characterization of an in vitro model of psoriasis.
In this study, the phenotype of psoriatic keratinocytes and fibroblasts in reconstructed skin models was compared to those constructed from normal cells. Characterization of this model by immunohistochemistry showed that classical markers of keratinocyte differentiation exhibited similar patterns of distribution in the psoriatic models to those derived from normal cells and generally reflected in vivo observations. Some crucial differences, however, were observed between normal and psoriatic models when pro-inflammatory gene expression and keratinocyte proliferation were investigated. Notably, the chemokine receptor CXCR2 was overexpressed in the psoriatic models, and, moreover, was localized to the granular layer of keratinocytes as seen in psoriasis in vivo. Pro-inflammatory genes (tumor necrosis factor alpha [TNF-alpha], interferon gamma [IFN-gamma], and interleukin 8 [IL-8]) were expressed at high levels in the psoriatic models, but were only minimally expressed in the normal models. Models derived from uninvolved psoriatic skin showed the same gene expression profile as those derived from involved skin along with an increased proliferation rate when compared to normal models. These results suggest that psoriatic individuals possess an inherent predisposition to develop the disease phenotype even in the absence of T cells. This study represents a comprehensive characterization of psoriatic human skin reconstructed in vitro, and demonstrates the potential of this model as a valuable tool in drug discovery.
Cascade Biologics, Inc., Portland, Oregon, USA.
Carol L
CL
Barker
Mark T
MT
McHale
Angela K
AK
Gillies
John
J
Waller
David M
DM
Pearce
Joy
J
Osborne
Peter E
PE
Hutchinson
Gill M
GM
Smith
James H
JH
Pringle
D000328:Adult; D000368:Aged; D000918:Antibody Specificity; D002478:Cells, Cultured; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D015603:Keratinocytes / Q000166:cytology* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009924:Organ Culture Techniques / Q000379:methods*; D010641:Phenotype; D011565:Psoriasis / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology*; D023062:Receptors, Interleukin-8A / Q000235:genetics / Q000276:immunology; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma