Accepted: 13 April 2017

DOI: 10.1111/exd.13370

ORIGINAL ARTICLE

A novel JAK inhibitor JTE-­052 reduces skin inflammation and

ameliorates chronic dermatitis in rodent models: Comparison
with conventional therapeutic agents

Atsuo Tanimoto1  | Yuichi Shinozaki1 | Yasuo Yamamoto1 | Yoshiaki Katsuda1 | 

Eriko Taniai-Riya2 | Kaoru Toyoda2 | Kochi Kakimoto2 | Yukari Kimoto1 | 
Wataru Amano1 | Noriko Konishi1 | Mikio Hayashi1

1
Biological/Pharmacological Research
Laboratories, Central Pharmaceutical Research
Institute, Japan Tobacco Inc., Takatsuki, Osaka,
Japan
2
Toxicology Research Laboratories, Central
Pharmaceutical Research Institute, Japan
Tobacco Inc., Hadano, Kanagawa, Japan
Correspondence
Atsuo Tanimoto, Biological/Pharmacological
Research Laboratories, Central Pharmaceutical
Research Institute, Japan Tobacco Inc.,
Takatsuki, Osaka, Japan.
Email: atsuo.tanimoto@jt.com
Abstract
Janus kinases (JAKs) are required for several inflammatory cytokine signalling path-
ways and are implicated in the pathogenesis of chronic dermatitis, including atopic
dermatitis and psoriasis. JAK inhibitors are therefore promising therapeutic candidates
for chronic dermatitis. In this study, we evaluated the effects of the novel JAK inhibi-
tor JTE-­052 on inflammatory responses associated with chronic dermatitis, and com-
pared its profile with those of conventional therapeutic agents in rodent models of
chronic dermatitis. JTE-­052 inhibited the Th1-­, Th2-­and Th17-­type inflammatory re-
sponses of human T cells and mast cells in vitro. Oral administration of JTE-­052 inhib-
ited skin inflammation in hapten-­induced chronic dermatitis in mice, associated with
reduced levels of inflammatory cytokines in the skin and immunoglobulin (Ig) E in
serum. In contrast, although ciclosporin partly inhibited skin inflammation, it did not
reduce interleukin (IL)-­4 production in skin, and enhanced IgE production in serum.
Oral administration of JTE-­052 also inhibited skin inflammation in mouse models of
atopic dermatitis and psoriasis induced by a mite extract, thymic stromal lymphopoi-
etin or IL-­23. The maximal efficacy of JTE-­052 in these dermatitis models was superior
to the conventional therapeutic agents, ciclosporin and methotrexate. Topical applica-
tion of JTE-­052 ointment ameliorated hapten-­induced chronic dermatitis in rats more
effectively than tacrolimus ointment. Furthermore, JTE-­052 ointment did not cause
the thinning of normal skin associated with topical corticosteroids. These results indi-
cate that JTE-­052 is a promising candidate as an anti-­inflammatory drug for various
types of chronic dermatitis, with a distinctly different profile from conventional ther-
apy following either oral or topical application.

KEYWORDS
atopic dermatitis, corticosteroids, cytokine signalling, immunosuppressants, psoriasis

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2017 The Authors. Experimental Dermatology Published by John Wiley & Sons Ltd.

22  |  wileyonlinelibrary.com/journal/exd Experimental Dermatology. 2018;27:22–29.

TANIMOTO et al.
1 | INTRODUCTION
Atopic dermatitis (AD) and psoriasis are the most common chronic
inflammatory skin diseases.[1,2] They are characterised pathophysio-
logically by disrupted skin homeostasis and dysregulated immune re-
[3,4]
sponse. Several medications are used to treat these diseases with
the aim of reducing skin inflammation.[5-8] Topical steroids and topical
immunosuppressants are the main agents used for chronic dermatitis,
and show definite therapeutic effects; however, their value is limited by
[5,7]
local side effects and insufficient efficacy. Oral steroids or immuno-
suppressants such as methotrexate and ciclosporin may also be used in
patients with moderate-­to-­severe symptoms, but their usage is limited
by systemic side effects.[6,8] Novel therapies with fewer side effects are
therefore needed for the effective treatment of chronic dermatitis.
Biologics such as antitumor necrosis factor (TNF) monoclonal an-
tibody,[9] ustekinumab[10] and secukinumab,[11] which have been ap-
proved for psoriasis, and dupilumab,[12] which is under development for
AD, have recently shown impressive results with good efficacy in clini-
cal trials. These trials suggested that inhibition of inflammatory cytokine
signal transduction may offer a promising approach to the treatment
of chronic dermatitis. Janus kinases (JAKs) comprise a non-­receptor-­
type tyrosine kinase family composed of four enzymes (JAK1, JAK2,
JAK3 and Tyk2), which transduce signals from multiple type I and type
II cytokine receptors and mediate various inflammatory responses.[13]
Various JAK-­related cytokines play roles in the pathophysiology of pso-
riasis (interleukin (IL)-­12, IL-­23, IL-­22) and AD (IL-­4, IL-­13, IL-­31, thy-
mic stromal lymphopoietin (TSLP)).[14] Inhibition of JAKs may therefore
represent a novel therapeutic approach for chronic dermatitis. Indeed,
clinical trials of JAK inhibitors in patients with chronic dermatitis have
[15,16]
already demonstrated definite effectiveness. Furthermore, a pre-
clinical study also reported efficacy of a JAK inhibitor in animal models
of chronic dermatitis.[17–20] However, the difference between conven-
tional therapies and JAK inhibitors has not been fully investigated.
We recently developed a novel JAK inhibitor, JTE-­052, that was
[21]
shown to be orally active and more potent than tofacitinib in mice.
In this study, we investigated the efficacy of oral JTE-­052 in several
rodent models of chronic dermatitis, and compared its profile with
conventional therapeutic agents. We also investigated the efficacy of
topical application of JTE-­052 ointment in chronic dermatitis model,
in the light of the likely reduced risk of systemic side effects of this
mode of application.
2 | MATERIALS AND METHODS
2.1 | Animals
Balb/c mice were obtained from Japan SLC, Inc. (Hamamatsu, Japan).
C57BL/6 mice, Nc/Nga mice and BN rats were obtained from Charles
River Japan, Inc. (Yokohama, Japan). Animals were maintained under spe-
cific pathogen-­free conditions at a room temperature of 23±3°C and air
humidity of 55±15% with a 12-­h/12-­h light/dark cycle. All procedures re-
lated to the use of animals in this study were reviewed and approved by
the Institutional Animal Care and Use Committee of Japan Tobacco Inc.
|
      23
2.2 | Compounds
JTE-­
052 was synthesised at the Central Pharmaceutical Research
Institute, Japan Tobacco Inc. (Osaka, Japan). JTE-­052 inhibited JAK1,
JAK2, JAK3 and Tyk2 with IC50 values of 2.8, 2.6, 13 and 58 nM, re-
spectively, in enzyme assays, and inhibited IL-­2, IL-­6, IL-­23, IFN-­α and
GM-­CSF signalling in analogy with other JAK inhibitors such as tofaci-
tinib in cellular assays.[21] Ciclosporin was purchased from Wako Pure
Chemical Industries, Ltd. (Osaka, Japan). Methotrexate hydrate was
purchased from Sigma-­Aldrich (St. Louis, MO, USA). Tacrolimus oint-
ment 0.1% (protopic) and difluprednate ointment 0.05% (Myser) were
purchased from Astellas Pharma Inc. (Tokyo, Japan) and Mitsubishi
Tanabe Pharma Corporation (Osaka, Japan), respectively. For the in
vitro experiments, JTE-­052 was dissolved in dimethyl sulfoxide and
diluted with the buffer used in each experiment. For the in vivo ex-
periments, JTE-­052, ciclosporin and methotrexate were suspended
in 0.5% (w/v) methylcellulose solution for oral administration or dis-
persed in petrolatum-­based ointment for topical administration.
2.3 | Cellular assay
Human peripheral blood was obtained from healthy volunteers with
informed consent, based on the Declaration of Helsinki. Human
memory CD4+ T cells were isolated from peripheral blood using
Lymphoprep™ and a human memory CD4+ T cell isolation kit (Miltenyi
Biotec Inc., Bergisch Gladbach, Germany). For determination of cy-
tokine production by memory CD4+ T cells, human memory CD4+ T
cells were plated at 1×105 cells/well in 96-­well plates coated with
3 μg/mL anti-­CD3 antibody (Affymetrix, Inc., Santa Clara, CA, USA)
with 3 μg/mL soluble anti-­CD28 (BD Biosciences, San Jose, CA, USA)
in the presence or absence of JTE-­052 for 3 days. The supernatant
was collected, and IL-­4, IL-­13, interferon (IFN)-­γ, IL-­17 and IL-­22 were
measured by ProcartaPlex Multiplex Immunoassays (Affymetrix, Inc.).
Human mast cells were obtained from CD34+ cord blood cells (Lonza
Walkersville Inc., Walkersville, MD, USA) by culture in the presence of
stem cell factor, IL-­6 and IL-­3 for 10 days, followed by stem cell factor
and IL-­6 for 8 weeks. For determination of IL-­13 production by mast
cells, human mast cells were plated in 96-­well plates at 2×105 cells/
well in the presence or absence of JTE-­052. Following preincubation
with the compound for 10 minutes, the cells were stimulated by add-
ing 10 ng/mL recombinant human IL-­4 and 1 μg/mL immunoglobulin
(Ig) E for 5 days. The cells were then replated at 1.2×105 cells/well,
and cultured with 1 μg/mL anti-­IgE for an additional 5 hours. The su-
pernatants were collected, and IL-­13 was measured by enzyme-­linked
immunosorbent assay (ELISA) (GEN-­Probe Inc., San Diego, CA, USA).
2.4 | Hapten-­induced chronic dermatitis in mice
Hapten-­induced chronic dermatitis was induced in female BALB/c mice
as described previously.[22] Briefly, mouse ears were treated with 25 μL
of 0.15% 2, 4-­dinitrofluorobenzene (DNFB) dissolved in acetone/olive
oil (3:1) once a week for 5 weeks. Ear thickness as an index of ear swell-
ing was measured with a digital thickness gauge (Digimatic Indicator;
 |
24       TANIMOTO et al.
F I G U R E   1   JTE-­052 inhibits Th1-­, Th2-­ and Th17-­type responses
in memory T cells and mast cells. (A) Human memory T cells were
stimulated on plates coated anti-­CD3 (3 μg/mL) and soluble anti-­
CD28 (3 μg/mL) in the presence of JTE-­052 for 3 d, and cytokine
production was assessed. (B) Human cord blood mast cells were
stimulated with IL-­4 (10 ng/mL) and IgE (1 μg/mL) for 5 d in the
presence of JTE-­052, and stimulated with anti-­IgE antibody (1 μg/mL)
for an additional 5 h. IL-­13 levels in the supernatants were assessed.
Four independent experiments using cells from different donors were
performed. Data shown are means+standard deviation (n=3) from
one representative experiment. *P<.05, **P<.01 vs CD3/CD28 or
IgE/anti-­IgE+IL-­4-­treated cells by Dunnett’s test
Mitutoyo Corporation, Kawasaki, Japan) before and 24 hours after
DNFB application, and expressed as the increase in thickness from the
baseline measurement. JTE-­
052 and ciclosporin were administered
orally once a day from the day of first DNFB application. After the
last measurement of ear thickness, mice were anesthetised, and blood
samples were collected. The mice were then euthanised, and their ears
were excised for analysis of cytokine expression and histological evalu-
ation. Serum total IgE and anti-­2,4-­dinitrophenol (DNP)-­specific IgE lev-
els were assessed by ELISA (Shibayagi Co., Ltd. Shibukawa, Japan).[22]
Ear sections were homogenised, and cytokine levels in the supernatant
were assessed by ELISA (R&D Systems, Inc., Minneapolis, MN, USA).
2.5 | Mite extract-­and cytokine-­induced dermatitis
model in mice
Mite extract-­induced dermatitis was induced in female Nc/Nga mice as
described previously.[23] Briefly, 5 μg of Dermatophagoides pteronyssinus
extract (Cosmo Bio Co. Ltd., Tokyo, Japan) was injected intradermally
in the ears of mice three times a week for 3 weeks, and ear thickness
was measured 24 hours later. TSLP-­induced dermatitis was induced in
female C57BL/6 mice as described previously[18] with minor modifica-
tions. Briefly, 0.5 μg of recombinant mouse TSLP (R&D Systems, Inc.)
was injected intradermally in the ears of mice on days 1, 3, 5, 8 and 10,
and ear thickness was measured 24 hours after each injection. IL-­23-­
induced dermatitis was induced in female C57BL/6 mice as described
previously[24] with minor modifications. Briefly, 0.25 μg of recombinant
mouse IL-­23 (R&D Systems, Inc.) was injected intradermally in the ears of
mice on days 1, 3, 5, 8 and 10, and ear thickness was measured on days 1,
3, 5, 8, 10 and 12. In each model, JTE-­052, ciclosporin and methotrexate,
respectively, were administered orally from the day of the first injection.
2.6 | Hapten-­induced chronic dermatitis model
in Rat
Hapten-­induced chronic dermatitis was induced in male DN rats as de-
scribed previously[25] with minor modifications. Briefly, rat ears were
treated with 30 μL of 0.5% 2, 4-­dinitrochlorobenzene (DNCB) dis-
solved in acetone/olive oil (4:1) on days 1, 3, 7, 9, 12, 14, 16, 19 and 21.
Ear thickness was measured as an index of ear swelling 6 hours after
DNCB application, and expressed as the increase in thickness from
baseline. JTE-­052 ointment, tacrolimus ointment or difluprednate oint-
ment was administered topically once a day from the day of first DNCB
application. After the last measurement of ear thickness, rats were eu-
thanised, and their ears were excised for histological evaluation.
2.7 | Statistical analysis
Data are expressed as the mean+standard deviation of the indicated
number of samples. The significance of differences between two
groups was assessed by Student’s t-tests (for homoscedastic data) or
Aspin-­Welch t-tests (for heteroscedastic data), after homoscedasticity
analysis by F-tests. Differences among multiple groups were analysed
by Dunnett’s tests (for homoscedastic data) or Steel’s tests (for het-
eroscedastic data) after homoscedasticity analysis by Bartlett’s test.
3 | RESULTS
3.1 | JTE-­052 inhibits inflammatory responses
including Th1-­, Th2-­ and Th17-­type responses
Th1, Th2 and Th17-­type responses are thought to be involved in sev-
eral chronic dermal diseases.[14] We therefore used a cell-­based assay
TANIMOTO et al.
to determine which type of Th response could be reduced by JTE-­052.
Regarding T cells, anti-­CD3/CD28 stimulation increased the Th-­type
+
cytokines IFN-­γ, IL-­4, IL-­13, IL-­17A and IL-­22 in human memory CD4
T cells after 3 days of incubation, all of which were dose-­dependently
inhibited by JTE-­052 (Figure 1A). We also investigated the inhibitory
|
      25
F I G U R E   2   Oral administration of JTE-­052 inhibits skin
inflammation in hapten-­induced chronic dermatitis in mice. Mice
received topical application of 0.15% DNFB in acetone/olive oil
or vehicle (sham [S]) on the ear once a week for 5 wk. Vehicle (V),
JTE-­052 (0.3, 3, or 30 mg/kg) or ciclosporin (Cs; 30 mg/kg) was
administered orally once daily for 29 d from the day of first DNFB
application. (A) Ear thickness was assessed before and 24 h after the
fifth DNFB application. Data were expressed as the increase in ear
thickness from baseline. (B) Histological analysis at 24 h after the
fifth DNFB application. (C) Cytokine expression in ear tissues 4 h
(IL-­13 and TNF-­α) and 24 h (IL-­4) after the fifth DNFB application.
(D) Total IgE and anti-­DNP IgE levels in serum at day 30. The results
are expressed as mean+standard deviation (n=10). *P<.05, **P<.01 vs
vehicle by Dunnett’s test. #P<.05, ##P<.01 vs vehicle by Steel’s test
effect of JTE-­052 on Th-­related cytokine production in non-­T cells.
Mast cells have been reported to play an important role in the patho-
genesis of allergic diseases by producing Th2-­type cytokines.[26] We
therefore determined the effect of JTE-­052 on mast cells. JTE-­052
dose-­dependently inhibited IL-­13 production from human cord blood-­
derived mast cells stimulated with IL-­4 and IgE/anti-­IgE (Figure 1B).
These results indicated that JTE-­052 inhibited Th1-­, Th2-­and Th17-­
type cytokine production from both T cells and non-­T cells.
3.2 | JTE-­052 inhibits skin inflammation in hapten-­
induced chronic dermatitis after oral administration
The repeated hapten-­induced chronic dermatitis model is considered
to involve Th2 cells and mast cells and is a useful model of human
AD.[27,28] To determine if JTE-­052 reduced skin inflammation in chronic
dermatitis, we examined its effect on DNFB-­induced chronic dermatitis
in mice. Repeated topical application of DNFB to mouse ears induced
ear swelling from 24 hours after the second application, and ear thick-
ness increased in proportion to the number of exposures to DNFB.
Oral administration of JTE-­052 at doses of 0.3-­30 mg/kg was well tol-
erated (even 100 mg/kg was tolerated; data not shown), and inhibited
the ear swelling in a dose-­dependent manner. Ciclosporin also inhib-
ited the ear swelling at 30 mg/kg (maximal tolerable dose in mice, data
not shown), JTE-­052 was more effective than 30 mg/kg ciclosporin at
doses of 3 and 30 mg/kg (Figure 2A). Histopathologically, acanthosis
and spongiosis in the epidermis and infiltration of inflammatory cells
in the dermis were observed in DNFB-­
stimulated, vehicle-­
treated
mice. Oral administration of JTE-­052 reduced the severity of the his-
topathological changes in a dose-­dependent manner, while ciclosporin
had no effect on any of the histopathological changes (Figure 2B). We
investigated inflammatory cell activation in this model by measuring
inflammatory cytokine levels in ear skin. IL-­4, IL-­13 and TNF-­α levels
were increased in the vehicle-­treated group after the fifth application
of DNFB. JTE-­052 inhibited the increases in all these cytokine levels
(Figure 2C). To investigate antibody production, we also determined
total IgE levels and “hapten-­specific” anti-­DNP IgE in the serum after
the fifth application of DNFB. Total and anti-­DNP IgE were increased
in the vehicle group, and JTE-­052 inhibited the increase in total and
anti-­DNP IgE (Figure 2D). Ciclosporin reduced the increases in IL-­13
 |
26       TANIMOTO et al.

and TNF-­α levels in ear skin but had no effect on IL-­4. Moreover, ciclo- corticosteroid difluprednate ointment 0.05% inhibited DNCB-­induced
sporin potentiated serum anti-­DNP IgE levels in this model, consistent ear swelling (Figure 4C). We also investigated the local side effect of
with a previous report.[22] the ointments on normal rat skin. Treatment with JTE-­052 ointment
3% for 22 days on the ear had no effect on normal ear thickness. In

3.3 | Comparison of efficacies of oral JTE-­052 and

conventional therapy in AD-­like and psoriasis-­like
dermatitis in mice
We examined the effects of JTE-­052 on other chronic dermatitis
models related to AD and psoriasis, and compared its efficacy with
conventional therapeutic agents used to treat these diseases. Mite
extract-­induced dermatitis in mice involves AD-­like skin lesions and
like pathophysiology.[23] TSLP-­induced
is reported to have an AD-­
dermatitis is also associated with the pathobiology of AD.[18] We
therefore determined the effects of JTE-­052 in these AD models.
Repeated intradermal injection of mite extract or TSLP in mouse ears
increased ear swelling at 24 hours after the second injection, and ear
thickness increased in proportion to the number of injections in the
vehicle-­
treated mice. Oral administration of JTE-­
052 reduced ear
swelling in a dose-­dependent manner in both AD models, while the
conventional agent for severe AD, ciclosporin, showed no clear inhibi-
tory effect even at the maximal tolerated dose of 30 mg/kg in these
models (Figure 3A,B). IL-­23-­induced dermatitis in mice has been re-
ported to have a psoriasis-­like pathophysiology,[24] and we therefore
investigated the effect of JTE-­052 in this model. Repeated intrader-
mal injection of IL-­23 in mouse ears caused ear swelling 48 hours after
the second injection, and ear thickness increased in proportion to the
number of injections. Oral administration of JTE-­052 inhibited the ear
swelling in a dose-­dependent manner (Figure 3C). Methotrexate in-
hibited the increase in ear thickness at the maximal tolerated dose for
mice of 1 mg/kg (data not shown). The efficacy of JTE-­052 at doses of
3 and 30 mg/kg was superior to that of 1 mg/kg methotrexate.

3.4 | Topical JTE-­052 ointment ameliorates hapten-­

induced chronic dermatitis in rats
We investigated the effect of topical administration of JTE-­
052
ointment on skin inflammation in a rat model of chronic dermatitis.
Repeated application of DNCB-­induced ear swelling from 6 hours
after the third application, and ear thickness increased in proportion to
the number of exposures to DNCB, reaching a plateau at the seventh
application in placebo-­treated or non-­treated rats. Topical administra-
tion of JTE-­052 ointment inhibited the increase in ear thickness in
a concentration-­dependent manner (Figure 4A). Histopathologically,
acanthosis and spongiosis in the epidermis and infiltration of inflam-
F I G U R E   3   JTE-­052 ameliorates AD-­like and psoriasis-­like
matory cells in the dermis were prominently observed in the placebo dermatitis in mice. Mice received intradermal injections of (A) 5 μg
ointment-­treated rats. Topical administration of JTE-­052 ointment mite extract, (B) 0.5 μg TSLP or (C) 0.25 μg IL-­23 in the ear three
reduced the severity of the histopathological changes in a dose-­ times a week for 2 or 3 wk. Vehicle, JTE-­052 (0.3, 3, or 30 mg/kg),
dependent manner (Figure 4B). Tacrolimus ointment 0.1% reduced ciclosporin (30 mg/kg) or methotrexate (0.3 mg/kg) was administered
orally once daily from the day of first substrate injection. Ear
ear thickness and the severity of the histopathological changes in
thickness was assessed over time and expressed as the increase in
DNCB-­induced dermatitis without affecting normal skin thickness.
thickness from baseline. The results are expressed as mean+standard
The efficacies of JTE-­052 ointment at 0.3% or 3% were superior to deviation (n=6-­12). *P<.05, **P<.01 vs vehicle by Dunnett’s test.
#
tacrolimus ointment 0.1% (Figure 4A,C). Administration of the topical P<.05, ##P<.01 vs vehicle by Steel’s test
TANIMOTO et al.
contrast, difluprednate ointment 0.05% decreased ear thickness in
normal rats (Figure 4D). These results indicate that JTE-­052 ointment
reduced ear swelling in a DNCB-­induced dermatitis model at a con-
centration that did not affect normal skin thickness.
|
      27
F I G U R E   4   Topical application of JTE-­052 ointment ameliorates
hapten-­induced chronic dermatitis in rats. Rats received topical
application of 0.5% DNCB in acetone/olive oil or vehicle on the ear
three times a week for 3 wk. JTE-­052 ointment (placebo, 0.03%,
0.3% or 3%) or tacrolimus ointment (0.12%) was administered
topically once daily for 20 d from the day of first DNCB application.
(A) Ear thickness was assessed 6 h after DNCB application and
expressed as the increase in thickness from baseline. (B) Histological
analysis on day 21. (C) Effect of difluprednate ointment 0.05% on
hapten-­induced chronic dermatitis was determined in a separate
experiment. (D) Normal rats were administered topical JTE-­052
ointment (placebo, 3%), tacrolimus ointment 0.1% or difluprednate
ointment 0.05%, and ear thickness was assessed on day 21. The
results are expressed as mean+standard deviation (n=6-­9). NA: non-­
administration *P<.05, **P<.01 vs placebo by Dunnett’s test. #P<.05,
##
P<.01 vs placebo by Steel’s test. $$P<.01 vs non-­administration by
Student’s t test. ++P<.01 vs non-­administration by Aspin-­Welch t test
4 | DISCUSSION
In this study, we investigated the effects of the novel JAK inhibitor
JTE-­052 on chronic dermatitis in rodent models, and compared it
with existing therapeutic agents. Oral administration of JTE-­052 in-
hibited skin inflammation in various types of dermatitis, along with
suppression of inflammatory cell activation. The maximal efficacy of
oral JTE-­052 in skin inflammation was superior to that of ciclosporin
and methotrexate in dermatitis models related to AD and psoriasis.
Topical administration of JTE-­
052 ointment was also effective in
chronic dermatitis, and its efficacy was superior to tacrolimus oint-
ment. Furthermore, it did not cause the thinning of normal skin as-
sociated with topical corticosteroids such as difluprednate ointment.
In this study, oral administration of JTE-­052 improved skin inflam-
mation in all the tested models of chronic dermatitis. In contrast, the
T cell activation inhibitor ciclosporin only reduced skin inflammation in
hapten-­induced chronic dermatitis in mice and had little effect on mite
extract-­induced or TSLP-­induced AD-­like dermatitis. Cutaneous T cells
have been reported to contribute to skin inflammation in a hapten-­
induced chronic allergic dermatitis model.[22] However, although T cells
contribute to mite extract-­induced dermatitis,[29] mite components
can also induce local inflammation directly through the activation of
non-­T cells.[30,31] TSLP was also reported to induce the activation of
non-­T cells such as dendritic cells, mast cells and innate lymphoid cells
type 2 directly, but not T cells in the absence of antigens.[32] The rela-
tively minor contribution of T cells to the pathogenesis of mite extract-­
and TSLP-­induced dermatitis may thus explain the lack of efficacy of
ciclosporin in these models. However, unlike ciclosporin, JTE-­052 in-
hibited the activation of various types of inflammatory cells, includ-
ing non-­T cells and T cells, and demonstrated beneficial effects in all
these dermatitis models. The different efficacies of methotrexate and
JTE-­052 in IL-­23-­induced dermatitis may have a similar explanation.
Several pharmacological mechanisms of action have been proposed
for methotrexate, and its anti-­inflammatory effect has largely been at-
tributed to the reduction of conventional T cell proliferation.[33] The
partial efficacy of methotrexate in IL-­23-­induced dermatitis might thus
 |
28       TANIMOTO et al.
be explained by its limited effect on non-­T cells. Overall, these find-
ings indicate that JTE-­052 exerts anti-­inflammatory effects in different
types of dermatitis by inhibiting various types of inflammatory cells.
In this study, serum IgE levels were increased by ciclosporin in
a hapten-­induced dermatitis model, as described previously.[22] In a
previous report, selective inhibition of Th1 but not Th2 by ciclosporin
in vivo enhanced Th2-­induced IgE production. Similarly, ciclosporin
failed to inhibit IL-­4 production in the ear in the current study, suggest-
ing that partial inhibition of the Th response enhanced IgE production
in this hapten-­induced dermatitis model. In contrast, JTE-­052 reduced
IL-­4 production in the ear in this model, consistent with inhibition of
IL-­4 in vitro, indicating that JTE-­052 inhibited Th2 cells in vivo. In addi-
tion, we previously revealed that JTE-­052 inhibited B-­cell proliferation
induced by IL-­21, a cytokine indispensable for the germinal centre re-
action,[21] suggesting that its direct inhibitory effect on B cells might
contribute to the decrease in serum IgE production induced by JTE-­
052. These findings might explain the difference between ciclosporin
and JTE-­052 in terms of their effects on serum IgE production. IgE is
considered to play an important role in the pathogenesis of allergic
diseases such as AD.[34] Indeed, in contrast to ciclosporin that showed
reduced efficacy in the late phase of the experiment in association
with serum IgE elevation, the effect of JTE-­052 on ear swelling lasted
throughout the experiment in hapten-­
induced dermatitis in mice.
Taken together, these findings indicate that JTE-­052 may have distinct
therapeutic effects from ciclosporin in these diseases via inhibition of
IgE production.
Systemic immunomodulating agents such as ciclosporin and meth-
otrexate are prevalent treatment options for the management of se-
vere symptoms in patients with AD and psoriasis, but their usage is
limited by organ toxicities including nephrotoxicity, hepatotoxicity
and pulmonary fibrosis.[6,35] In contrast, there have been no notice-
able reports of organ toxicity associated with systemic JAK inhibi-
tors in several clinical trials.[36] JAK inhibitors may therefore offer a
beneficial systemic medication option for chronic dermatitis, with a
lower risk of side effects than conventional systemic agents. However,
systemic administration of JAK inhibitors is associated with potential
risks of infection and malignancies, as for other systemic agents,[37]
and topical application of JAK inhibitors may thus offer a preferable
option for chronic dermatitis. Although topical corticosteroids and
calcineurin inhibitors are widely used for treating chronic dermatitis
without systemic toxicity, they are associated with a risk of local cuta-
neous side effects such as skin atrophy.[38] Indeed, topical administra-
tion of the corticosteroid difluprednate ointment 0.05% in the current
study reduced skin thickness in normal rats, while topical treatment
of JTE-­052 ointment 3% had no effect on normal skin, but showed
comparable efficacy to difluprednate ointment in terms of skin in-
flammation in a DNCB-­induced rat dermatitis model. In addition, it
was recently recognised that skin barrier disruption contributes to
the pathophysiology of chronic dermatitis, such as AD.[39,40] As JAK
inhibition by JTE-­052 was revealed to improve skin barrier disruption
by directly affecting epidermal keratinocytes in our previous study,[20]
topical application may be an effective dosage form for this JAK inhib-
itor to exert its effects on the skin barrier function. Topical application
of JTE-­052 may therefore be an effective novel therapy for chronic
dermatitis, with a better risk profile than conventional therapies.
In conclusion, the results of this study demonstrate that JTE-­
052, by either oral or topical application, is a good candidate as an
anti-­inflammatory drug for the treatment of various types of chronic
dermatitis, including AD and psoriasis, with a distinct profile from con-
ventional therapies.
AC KNOW L ED G EM ENTS
We would like to express our gratitude to Yuichi Naka (Japan Tobacco
Inc.) for helpful discussion.
CO NFL I C TS O F I NT ER ES T
All authors of this manuscript are employees of Japan Tobacco Inc.
The authors declare that they have no other competing interests.
AU T HO R CO NT R I B U T I O NS
AT, YS, YY, YK (Yoshiaki Katsuda), ER, KT, KK and YK (Yukari Kimoto)
contributed to data acquisition and analysis. AT, YS, WA, NK and MH
contributed to the study design, data interpretation and writing of the
manuscript. All authors provided critical review of the draft manu-
script and approved submission of the final manuscript for publication.
ET HI C AL CO NS I D ER AT I O NS
All procedures related to the use of animals in this study were re-
viewed and approved by the Institutional Animal Care and Use
Committee of Japan Tobacco Inc. Human peripheral blood was ob-
tained from healthy volunteers with informed consent, based on the
Declaration of Helsinki.
REFERENCES
[1] J. G. Krueger, A. Bowcock, Ann. Rheum. Dis.2005, 64 (Suppl 2), ii30.
[2] T. Bieber, N. Engl. J. Med. 2008, 358, 1483.
[3] E. Guttman-Yassky, K. E. Nograles, J. G. Krueger, J. Allergy Clin.
Immunol. 2011, 127, 1110.
[4] E. Guttman-Yassky, K. E. Nograles, J. G. Krueger, J. Allergy Clin.
Immunol. 2011, 127, 1420.
[5] J. Ring, A. Alomar, T. Bieber, M. Deleuran, A. Fink-Wagner, C.
Gelmetti, U. Gieler, J. Lipozencic, T. Luger, A. P. Oranje, T. Schafer, T.
Schwennesen, S. Seidenari, D. Simon, S. Stander, G. Stingl, S. Szalai,
J. C. Szepietowski, A. Taieb, T. Werfel, A. Wollenberg, U. Darsow,
European Dermatology Forum, European Academy of Dermatology,
Venereology, European Federation of Allergy, European Task Force on
Atopic Dermatitis, European Society of Pediatric Dermatology, Global
Allergy, Asthma European Network. J. Eur. Acad. Dermatol. Venereol.
2012, 26, 1045.
[6] J. Ring, A. Alomar, T. Bieber, M. Deleuran, A. Fink-Wagner, C.
Gelmetti, U. Gieler, J. Lipozencic, T. Luger, A. P. Oranje, T. Schafer, T.
Schwennesen, S. Seidenari, D. Simon, S. Stander, G. Stingl, S. Szalai,
J. C. Szepietowski, A. Taieb, T. Werfel, A. Wollenberg, U. Darsow,
European Dermatology Forum, European Academy of Dermatology,
Venereology, European Task Force on Atopic Dermatitis, European
TANIMOTO et al.
Federation of Allergy, European Society of Pediatric Dermatology,
Global Allergy, Asthma European Network. J. Eur. Acad. Dermatol.
Venereol. 2012, 26, 1176.
[7] A. Menter, N. J. Korman, C. A. Elmets, S. R. Feldman, J. M. Gelfand,
K. B. Gordon, A. Gottlieb, J. Y. Koo, M. Lebwohl, H. W. Lim, A. S. Van
Voorhees, K. R. Beutner, R. Bhushan, J. Am. Acad. Dermatol. 2009, 60,
643.
[8] A. Menter, N. J. Korman, C. A. Elmets, K. R. Beutner, R. Bhushan, J. Am.
Acad. Dermatol. 2009, 61, 451.
[9] A. Menter, A. Gottlieb, S. R. Feldman, A. S. Van Voorhees, C. L. Leonardi,
K. B. Gordon, M. Lebwohl, J. Y. Koo, C. A. Elmets, N. J. Korman, K. R.
Beutner, R. Bhushan, J. Am. Acad. Dermatol. 2008, 58, 826.
[10] C. L. Leonardi, A. B. Kimball, K. A. Papp, N. Yeilding, C. Guzzo, Y. Wang,
S. Li, L. T. Dooley, K. B. Gordon, Investigators Phoenix Study Lancet
2008, 371, 1665.
[11] D. Thaci, A. Blauvelt, K. Reich, T. F. Tsai, F. Vanaclocha, K. Kingo,
M. Ziv, A. Pinter, S. Hugot, R. You, M. Milutinovic, J. Am. Acad.
Dermatol. 2015, 73, 400.
[12] D. Thaci, E. L. Simpson, L. A. Beck, T. Bieber, A. Blauvelt, K. Papp,
W. Soong, M. Worm, J. C. Szepietowski, H. Sofen, M. Kawashima,
R. Wu, S. P. Weinstein, N. M. Graham, G. Pirozzi, A. Teper, E. R.
Sutherland, V. Mastey, N. Stahl, G. D. Yancopoulos, M. Ardeleanu,
Lancet 2016, 387, 40.
[13] J. J. O’Shea, R. Plenge, Immunity 2012, 36, 542.
[14] S. Noda, J. G. Krueger, E. Guttman-Yassky, J. Allergy Clin. Immunol.
2015, 135, 324.
[15] H. Bachelez, P. C. van de Kerkhof, R. Strohal, A. Kubanov, F. Valenzuela,
J. H. Lee, V. Yakusevich, S. Chimenti, J. Papacharalambous, J. Proulx, P.
Gupta, H. Tan, M. Tawadrous, H. Valdez, R. Wolk, Investigators O. P. T.
Compare. Lancet 2015, 386, 552.
[16] L. L. Levy, J. Urban, B. A. King, J. Am. Acad. Dermatol. 2015, 73,
395.
[17] R. Nakagawa, H. Yoshida, M. Asakawa, T. Tamiya, N. Inoue, R. Morita,
H. Inoue, A. Nakao, A. Yoshimura, J. Immunol. 2011, 187, 4611.
[18] J. S. Fridman, P. A. Scherle, R. Collins, T. Burn, C. L. Neilan, D. Hertel, N.
Contel, P. Haley, B. Thomas, J. Shi, P. Collier, J. D. Rodgers, S. Shepard,
B. Metcalf, G. Hollis, R. C. Newton, S. Yeleswaram, S. M. Friedman, K.
Vaddi, J. Invest. Dermatol. 2011, 131, 1838.
[19] M. G. Works, F. Yin, C. C. Yin, K. Shew, T. T. Tran, N. Dunlap, J. Lam,
T. Mitchell, J. Reader, P. L. Stein, A. D’Andrea, J. Immunol. 2014, 193,
3278.
[20] W. Amano, S. Nakajima, H. Kunugi, Y. Numata, A. Kitoh, G. Egawa, T.
Dainichi, T. Honda, A. Otsuka, Y. Kimoto, Y. Yamamoto, A. Tanimoto,
M. Matsushita, Y. Miyachi, K. Kabashima, J. Allergy Clin. Immunol.
2015, 136, 667 e667.
[21] A. Tanimoto, Y. Ogawa, C. Oki, Y. Kimoto, K. Nozawa, W. Amano, S.
Noji, M. Shiozaki, A. Matsuo, Y. Shinozaki, M. Matsushita, Inflamm.
Res. 2015, 64, 41.
[22] H. Nagai, H. Hiyama, A. Matsuo, Y. Ueda, N. Inagaki, K. Kawada, J.
Pharmacol. Exp. Ther. 1997, 283, 321.
|
      29
[23] T. Sasakawa, Y. Higashi, S. Sakuma, Y. Hirayama, Y. Sasakawa, Y.
Ohkubo, T. Goto, M. Matsumoto, H. Matsuda, Int. Arch. Allergy
Immunol. 2001, 126, 239.
[24] Y. Zheng, D. M. Danilenko, P. Valdez, I. Kasman, J. Eastham-Anderson,
J. Wu, W. Ouyang, Nature 2007, 445, 648.
[25] T. Sasakawa, Y. Sasakawa, Y. Ohkubo, S. Mutoh, Int. Immunopharmacol.
2005, 5, 503.
[26] A. Otsuka, K. Kabashima, Allergy 2015, 70, 131.
[27] N. Inagaki, H. Nagai, J. Pharmacol. Sci. 2009, 110, 251.
[28] H. Kitagaki, S. Fujisawa, K. Watanabe, K. Hayakawa, T. Shiohara, J.
Invest. Dermatol. 1995, 105, 749.
[29] Y. Tenda, M. Yamashita, M. Y. Kimura, A. Hasegawa, C. Shimizu, M.
Kitajima, A. Onodera, A. Suzuki, N. Seki, T. Nakayama, J. Allergy Clin.
Immunol. 2006, 118, 725.
[30] N. Asokananthan, P. T. Graham, D. J. Stewart, A. J. Bakker, K. A. Eidne,
P. J. Thompson, G. A. Stewart, J. Immunol. 2002, 169, 4572.
[31] T. Heiberg, T. K. Kvien, Arthritis Rheum. 2002, 47, 391.
[32] A. Cianferoni, J. Spergel, Expert Rev. Clin. Immunol. 2014, 10, 1463.
[33] C. H. Nielsen, L. Albertsen, K. Bendtzen, B. Baslund, Clin. Exp. Immunol.
2007, 148, 288.
[34] H. J. Gould, B. J. Sutton, Nat. Rev. Immunol. 2008, 8, 205.
[35] R. Sidbury, D. M. Davis, D. E. Cohen, K. M. Cordoro, T. G. Berger, J. N.
Bergman, S. L. Chamlin, K. D. Cooper, S. R. Feldman, J. M. Hanifin, A.
Krol, D. J. Margolis, A. S. Paller, K. Schwarzenberger, R. A. Silverman,
E. L. Simpson, W. L. Tom, H. C. Williams, C. A. Elmets, J. Block, C. G.
Harrod, W. S. Begolka, L. F. Eichenfield, J. Am. Acad. Dermatol. 2014,
71, 327.
[36] S. B. Cohen, A. Koenig, L. Wang, K. Kwok, C. A. Mebus, R. Riese, R.
Fleischmann, Clin. Exp. Rheumatol. 2016, 34, 32.
[37] D. M. Schwartz, M. Bonelli, M. Gadina, J. J. O’Shea, Nat. Rev.
Rheumatol. 2016, 12, 25.
[38] L. F. Eichenfield, W. L. Tom, T. G. Berger, A. Krol, A. S. Paller, K.
Schwarzenberger, J. N. Bergman, S. L. Chamlin, D. E. Cohen, K. D.
Cooper, K. M. Cordoro, D. M. Davis, S. R. Feldman, J. M. Hanifin, D. J.
Margolis, R. A. Silverman, E. L. Simpson, H. C. Williams, C. A. Elmets,
J. Block, C. G. Harrod, W. Smith Begolka, R. Sidbury, J. Am. Acad.
Dermatol. 2014, 71, 116.
[39] K. Kabashima, J. Dermatol. Sci. 2013, 70, 3.
[40] M. Schmuth, S. Blunder, S. Dubrac, R. Gruber, V. Moosbrugger-
Martinz, J. Dtsch. Dermatol. Ges. 2015, 13, 1119.
How to cite this article: Tanimoto A, Shinozaki Y, Yamamoto Y,
et al. A novel JAK inhibitor JTE-­052 reduces skin inflammation
and ameliorates chronic dermatitis in rodent models:
Comparison with conventional therapeutic agents. Exp Dermatol.
2018;27:22–29. https://doi.org/10.1111/exd.13370