Acta Dermato-Venereologica 97-10CompleteContent | Page 12
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INVESTIGATIVE REPORT
Increased Interleukin-19 Expression in Cutaneous T-cell Lymphoma
and Atopic Dermatitis
Tomonori OKA, Makoto SUGAYA, Naomi TAKAHASHI, Rina NAKAJIMA, Sayaka OTOBE, Miyoko KABASAWA, Hiraku SUGA,
Tomomitsu MIYAGAKI, Yoshihide ASANO and Shinichi SATO
Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
Interleukin-19 (IL-19), a pro-inflammatory cytokine
known to stimulate the production of T helper type 2
(Th2) cytokines, is induced by IL-17A and highly ex-
pressed in the lesional skin of psoriasis and atopic der-
matitis (AD). This aim of this study was to investigate
whether IL-19 is involved in cutaneous T-cell lym
phoma (CTCL) and AD. IL-19 levels were significantly
higher in the sera of patients with AD and those with
advanced-stage CTCL than in normal controls, corre-
lating significantly with clinical disease markers. IL-
19 mRNA levels in lesional skin of both diseases were
significantly elevated. Immunohistochemical staining
revealed that IL-19 was expressed in the epidermis of
AD skin and CTCL skin. In vitro, IL-17A and IL-4 in-
creased IL-19 mRNA expression in human keratino-
cytes. Thus, IL-19 was increased in the sera and skin
of AD and CTCL. These results suggest that IL-19 is
important for bridging Th17 to Th2 in these diseases.
Key words: IL-19; atopic dermatitis; cutaneous T-cell lympho-
ma; keratinocytes; IL-4; IL-17A.
Accepted Jun 8, 2017; Epub ahead of print Jun 9, 2017
Acta Derm Venereol 2017; 97: 1172–1177.
Corr: Makoto Sugaya, Department of Dermatology, the University of To-
kyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-
8655, Japan. E-mail: [email protected]
I
nterleukin (IL)-19 is a member of the so-called IL-10
family of cytokines. IL-19 was discovered in 2000
by means of a bioinformatics search for IL-10-related
molecules (1). Important cellular sources of IL-19 are
thought to be monocytes (1–3), keratinocytes (4–8) and
bronchial epithelial cells (9). IL-4 and IL-17A have
been reported to induce IL-19 expression by human
keratinocytes (4, 5, 7, 8). The IL-19 receptor consists
of IL-20R1 and IL-20R2 (10–12). The IL-19 subfamily
has 3 members, IL-19, IL-20 and IL-24, which have a
very similar tertiary structure (13) and are able to bind to
and signal through IL-20R1 and IL-20R2. Keratinocytes
express these receptors, suggesting that IL-19 can act in
an autocrine manner (8).
Many groups have documented increased IL-19 ex-
pression in the diseased skin of psoriasis in comparison
with non-diseased skin of the same patients or that of
healthy controls (4, 5, 14–16). IL-19 is also reported
to be up-regulated in lesional skin of atopic dermatitis
(AD) (4, 5). AD is a chronic inflammatory skin disease
that affects 10–20% of children and 1–3% of adults in
doi: 10.2340/00015555-2723
Acta Derm Venereol 2017; 97: 1172–1177
developed countries. It is well known that T helper type
2 (Th2) cells, expressing IL-4, IL-5, and IL-13, play
an essential role in the pathophysiology of AD (17).
IL-19 has been demonstrated to increase Th2 cytokine
expression in activated T cells (3, 18). Serum IL-19
levels are elevated in patients with asthma, suggesting
an essential role in the pathogenesis of asthma (18),
which is another Th2 cell-mediated disease. Serum IL-
19 levels in patients with AD, however, have not been
investigated previously.
Cutaneous T-cell lymphoma (CTCL) is a malignancy
of skin-trafficking T cells. Mycosis fungoides (MF) and
Sézary syndrome (SS) are the most common types of
CTCL. Prior studies have shown increased levels of
Th2 cytokines and Th2-associated genes in T cells from
patients with CTCL (19). Although up-regulated IL-19
in breast cancer has been shown to promote tumour
progression (20), little is known about an association
between IL-19 and other malignancies. IL-19 has not
been investigated for possible involvement in CTCL.
The aim of this study was therefore to examine serum
IL-19 levels and IL-19 expression in lesional skin of
AD and CTCL. A further aim was to investigate which
cytokines would induce IL-19 expression by normal
human keratinocytes.
MATERIALS AND METHODS
Tissue and serum samples
Messenger RNA (mRNA) was obtained from biopsy materials of
lesional skin of MF/SS (n = 17: patch MF 4, plaque MF 3, t umour
MF 5, erythrodermic MF 2, SS 3; mean ± standard deviation
(SD) age: 57.6 ± 12.7 years; 12 males and 5 females), AD (n = 7;
mean ± SD age: 36.3 ± 16.0 years; 5 males and 2 females), and
normal skin adjacent to benign skin tumours (n = 8; mean ± SD
age: 49.1 ± 21.0 years; 4 males and 4 females) using RNeasy Fi-
brous Tissue Mini Kit (QIAGEN, Valencia, CA, USA). Samples
for immunohistochemistry were lesional skin of MF/SS (n = 10:
patch MF 2, plaque MF 3, tumour MF 3, SS 2) or AD (n = 10),
and normal skin adjacent to benign skin tumours (n = 10). Serum
samples were obtained from 28 patients with MF/SS (patch MF 7,
plaque MF 10, tumour MF 9, erythrodermic MF 1, SS 1; mean ± SD
age: 54.5 ± 18.1 years; 15 males and 13 females), 35 patients
with AD (10 mild cases, 10 moderate cases, and 15 severe cases;
mean ± SD age: 30.8 ± 12.0 years; 23 males and 12 females), and
17 healthy control subjects (mean ± SD age: 47.6 ± 20.6 years; 11
males and 6 females). The healthy controls had no history of al-
lergy, AD, psoriasis, or CTCL. All samples were collected during
daily clinical practice in the University of Tokyo Hospital. The
medical ethics committee of the University of Tokyo approved
This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta
Journal Compilation © 2017 Acta Dermato-Venereologica.