MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte-associated antigen 4.
BACKGROUND
MicroRNAs (miRNAs) are short noncoding RNAs that suppress gene expression at the posttranscriptional level. Atopic dermatitis is a common chronic inflammatory skin disease characterized by the presence of activated T cells within the skin.


OBJECTIVE
We sought to explore the role of miRNAs in the pathogenesis of atopic dermatitis.


METHODS
Global miRNA expression in healthy and lesional skin of patients with atopic dermatitis was compared by using TaqMan MicroRNA Low Density Arrays. miR-155 expression in tissues and cells was quantified by means of quantitative real-time PCR. The cellular localization of miR-155 was analyzed by means of in situ hybridization. The regulation of cytotoxic T lymphocyte-associated antigen (CTLA-4) by miR-155 was investigated by using luciferase reporter assays and flow cytometry. CTLA-4 expression and functional assays were performed on T(H) cells overexpressing miR-155.


RESULTS
miR-155 was one of the highest-ranked upregulated miRNAs in patients with atopic dermatitis. In the skin miR-155 was predominantly expressed in infiltrating immune cells. miR-155 was upregulated during T-cell differentiation/activation and was markedly induced by T-cell activators in PBMCs in vitro and by superantigens and allergens in the skin in vivo. CTLA-4, an important negative regulator of T-cell activation, was identified as a direct target of miR-155. Overexpression of miR-155 in T(H) cells resulted in decreased CTLA-4 levels accompanied by an increased proliferative response.


CONCLUSIONS
miR-155 is significantly overexpressed in patients with atopic dermatitis and might contribute to chronic skin inflammation by increasing the proliferative response of T(H) cells through the downregulation of CTLA-4.
Sonkoly
Enikö
E
Dermatology and Venereology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. eniko.sonkoly@ki.se
Janson
Peter
P
Majuri
Marja-Leena
ML
Savinko
Terhi
T
Fyhrquist
Nanna
N
Eidsmo
Liv
L
Xu
Ning
N
Meisgen
Florian
F
Wei
Tianling
T
Bradley
Maria
M
Stenvang
Jan
J
Kauppinen
Sakari
S
Alenius
Harri
H
Lauerma
Antti
A
Homey
Bernhard
B
Winqvist
Ola
O
Ståhle
Mona
M
Pivarcsi
Andor
A
D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D060908:CTLA-4 Antigen; D049109:Cell Proliferation; D003876:Dermatitis, Atopic / Q000276:immunology*; D004285:Dogs; D015870:Gene Expression; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000737:chemistry / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; C524942:MIRN155 microRNA, human; D035683:MicroRNAs