Type I interferon: potential therapeutic target for psoriasis?
BACKGROUND
Psoriasis is an immune-mediated disease characterized by aberrant epidermal differentiation, surface scale formation, and marked cutaneous inflammation. To better understand the pathogenesis of this disease and identify potential mediators, we used whole genome array analysis to profile paired lesional and nonlesional psoriatic skin and skin from healthy donors.


RESULTS
We observed robust overexpression of type I interferon (IFN)-inducible genes and genomic signatures that indicate T cell and dendritic cell infiltration in lesional skin. Up-regulation of mRNAs for IFN-alpha subtypes was observed in lesional skin compared with nonlesional skin. Enrichment of mature dendritic cells and 2 type I IFN-inducible proteins, STAT1 and ISG15, were observed in the majority of lesional skin biopsies. Concordant overexpression of IFN-gamma and TNF-alpha-inducible gene signatures occurred at the same disease sites.


CONCLUSIONS
Up-regulation of TNF-alpha and elevation of the TNF-alpha-inducible gene signature in lesional skin underscore the importance of this cytokine in psoriasis; these data describe a molecular basis for the therapeutic activity of anti-TNF-alpha agents. Furthermore, these findings implicate type I IFNs in the pathogenesis of psoriasis. Consistent and significant up-regulation of type I IFNs and their associated gene signatures in psoriatic skin suggest that type I IFNs may be potential therapeutic targets in psoriasis treatment.
Yao
Yihong
Y
MedImmune, Inc., Gaithersburg, Maryland, United States of America. YaoY@MedImmune.com
Richman
Laura
L
Morehouse
Chris
C
de los Reyes
Melissa
M
Higgs
Brandon W
BW
Boutrin
Anmarie
A
White
Barbara
B
Coyle
Anthony
A
Krueger
James
J
Kiener
Peter A
PA
Jallal
Bahija
B
D001706:Biopsy; D002454:Cell Differentiation; D016000:Cluster Analysis; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D008954:Models, Biological; D011565:Psoriasis / Q000628:therapy*; D012333:RNA, Messenger / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D012867:Skin / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism
D016207:Cytokines; D007370:Interferon Type I; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014409:Tumor Necrosis Factor-alpha; D014452:Ubiquitins; C074034:ISG15 protein, human; D007371:Interferon-gamma