Critical role of the interleukin-23/T-helper 17 cell axis in the
pathogenesis of psoriasis
Department of Dermatology, Kochi Medical School, Kochi University, Kochi, Japan
Psoriasis is an inflammatory disease with dynamic interactions between the immune system and the skin. Recent studies
have demonstrated that the interleukin (IL)-23/T-helper (Th)17 cell axis plays an important role in the pathogenesis of
psoriasis. Here, the biology and function of Th17 cells as well as the crucial role of IL-23 in the context of the Th17 cell-
dependent chronic inflammation in psoriatic skins are reviewed. Recent study about the role of the IL-23/Th17 axis in the
pathogenesis of psoriasis-like lesions in K5.Stat3C transgenic mice is also discussed. This model mouse for psoriasis
not only verifies the therapeutic efficacies of biologics that specifically target the IL-23/Th17 axis, but also clarifies the
pathogenesis of psoriasis.
Key words:biologics, interleukin-23/T-helper 17 cell axis, mouse model, psoriasis, Stat3.
Psoriasis is one of the most common inflammatory disorders of
the skin and affects more than 2% of the population in Western
countries. The pathogenesis of psoriasis is multifactorial, with
genetic, environmental and immunological factors contributing
to the phenotype. It includes excessive proliferation and altered
differentiation of epidermal keratinocytes, likely mediated by the
immune system. Psoriatic lesions are characterized by histopatho-
logical changes including: (i) a thickened epidermis (acanthosis)
arising from rapid keratinocyte proliferation; (ii) a reduced or absent
granular layer (hypogranulosis) and retention of nuclei by coeno-
cytes (parakeratosis) due to the aberrant differentiation of keratino-
cytes; (iii) a marked dilation of blood vessels in the papillary
dermis, which causes visible erythema; and (iv) a dense inflamma-
tory infiltrate composed of clusters of CD4+Th cells and antigen-
presenting dendritic cells (DC) in the dermis and CD8+T cells and
neutrophils in the epidermis.
Our previous studies elucidated the role of Stat3 signaling in
keratinocytes during the development of psoriasis.1Furthermore,
transgenic mice expressing a constitutively active form of Stat3
(Stat3C) in their keratinocytes develop skin lesions that closely
resemble human psoriatic lesions. Those lesions develop either
spontaneously or in response to wounding or topical treatment with
the tumor promoter 12-0-tetradecanoylphorbol-13-acetate (TPA).
The psoriasis-like lesions in K5.Stat3C mice show histological find-
ingsand cytokineprofilessimilar tothoseof human plaquepsoriasis
(Fig. 1).1,2In addition, K5.Stat3C mice meet pharmacological criteria
and represent one of the most physiologically relevant animal mod-
els for psoriasis.3Further analyses showed a dual requirement for
both activated Stat3 in keratinocytes and activated T lymphocytes
in the development of psoriasis-like lesions.1
The success of targeted therapeutics, as well as advances in
genomic analyses, have further implicated immunological path-
ways in the pathogenesis of psoriasis. Furthermore, an explosion
of knowledge regarding T cells and DC associated with psoriasis
has shed more light on specific immune pathways that may be
crucial for its pathogenesis. The importance of T cells in the
pathogenesis of psoriasis is supported by the response of
patients to treatment with agents that affect T-cell function, such
as cyclosporine. Th1 cells had been long considered to be
exclusively important for psoriasis development, whereas Th2
cells are involved in atopic dermatitis. Although interferon (IFN)-
c+T cells are abundant in the peripheral blood and skin lesions
of psoriasis patients, the detailed role(s) for Th1 have remained
enigmatic. Th17 cells, newly discovered Th cells that exclusively
produce IL-17, have been recognized as the major players in
protective immunity against infection as well as in autoimmune
immune encephalomyelitis and psoriasis.4–8
T-helper 17 cells are distinct fromTh1 andTh2 cells in their differ-
entiation and maintenance conditions, as well as in their cytokine
profiles. Th17 cellshave also been shown to secreteother cytokines
in addition to IL-17, including IL-22, IL-21 and tumor necrosis factor
(TNF). A recent breakthrough in understanding the pathogenesis of
psoriasis has been made with studies that successfully linked the
IL-23⁄Th17 axis and keratinocytes.8–10Here, we highlight these
advancesintheassociation between theIL-23⁄Th17axisand kerat-
inocytes in the pathogenesis of psoriasis and consolidate them with
respect to our current studies using K5.Stat3C mice.
Correspondence: Kimiko Nakajima, Ph.D., M.D., Department of Dermatology, Kochi Medical School, Kochi University, 185-1 Kohasu, Okohcho,
Nankoku, Kochi, 783-8505, Japan. Email: email@example.com
Received 31 October 2011; accepted 1 November 2011.
doi: 10.1111/j.1346-8138.2011.01458.xJournal of Dermatology 2012; 39: 219–224
? 2012 Japanese Dermatological Association
ROLE OF IL-23 IN PSORIASIS
Interleukin-23 is a heterodimeric cytokine composed of p19
(encoded by IL-23A) and p40 (shared with IL-12 and encoded by
IL-12B) subunits, which binds to a receptor complex encoded by
IL-12Rb1 and IL-23R.11Both the IL-12Rb1 and IL-23R chains lack
intrinsic signaling activity and are associated with intracellular pro-
teins to induce downstream signaling. IL-12Rb1 binds to the Jak
family member Tyk2, whereas IL-23R associates with Jak2.12IL-23
stimulation resultsin ligand-induced autophosphorylationand trans-
homodimers translocate into the nucleus, where they bind to the
DNA in the promoter regions of the target genes.
Interleukin-23 is produced by DC and macrophages and is
required for the growth, survival and effecter functions of Th17 cells.
To investigate the cytokine profiles of human psoriatic lesions, we
compared transcriptional levels of cytokines from psoriatic lesions
with those from contiguous uninvolved skin. Similar to previous
reports, psoriatic lesions showed increased mRNA levels of the
IL-23⁄Th17 axis, including IL-23p19, IL-12⁄23p40, IL-17A, IL-17F
and IL-22, whereas mRNA levels of IL-12p35 and IL-4 were not
increased. p40 is the common subunit of IL-12 and IL-23, whereas
p19 and p35 are distinct subunits of IL-23 and IL-12, respectively.2
Our data is consistent with previous reports that IL-23p19 mRNA
expression is greater than IL-12p35 mRNA in human psoriasis.13
These data suggest that IL-23 plays a more dominant role than
IL-12 in psoriasis. IL-23p19 is mostly localized in the papillary der-
mis, and it is strongly expressed in monocytes, in monocyte-derived
DC and in mature DC. Further evidence for the role of IL-23 in the
pathogenesis of psoriasis is supported by observations of psoria-
sis-like acanthosis following repeated i.d. injections of IL-23 in
mice.8Collectively, these data indicate that the production of IL-23
occurs at inflammatory sites and is mediated by tissue-resident and
recruited immune cells, such as DC, and possibly by keratinocytes.
Recent studies have shown that polymorphisms in the IL-12⁄23p40
and IL-23R genes are associated with psoriasis.14These findings
risk of psoriasis.15
The most distinct evidence for the role of the IL-23⁄Th17 axis in
psoriasis comes from clinical studies. An anti-IL12⁄23p40 antibody,
(ustekinumab) has been used to treat moderate-to-severe plaque
psoriasis.16Because the p40 subunit is shared by IL-12 and IL-23,
ustekinumab inhibits both Th1 and Th17 cells. However, the
IL-23⁄Th17 axis is the predominant target of ustekinumab for the
amelioration of psoriasis based on the studies mentioned above.
TNF inhibitors are also widely used to treat autoimmune diseases,
including Crohn’s disease, Behc ¸et’s disease and psoriasis. Like
ustekinumab, TNF inhibitors also target the IL-23⁄Th17 axis for
amelioration of psoriasis.17,18We also demonstrated a role for IL-23
in psoriasis, evidenced by the comparable efficacy of antibodies to
IL-12⁄23p40 and IL-23p19 on the development of psoriasis-like
lesions in K5.Stat3C mice (Fig. 2).2Treatment with anti-IL-12⁄23p40
or anti-IL23p19 antibodies markedly lowered mRNA transcript
levels of Th17 cytokines (e.g. IL-17, IL-22), b-defensin and S100A
family members in skin lesions. These data indicate that IL-23 is
upstream of Th17 and is sufficient to initiate the development of
ROLE OF IL-17 IN PSORIASIS
A previous study demonstrated that IL-17 mRNA expression is
detectable in lesional psoriatic skin, but not in non-lesional control
skin.19They also showed that the majority of CD4+and CD8+T cell
clones derived from lesional psoriatic skin express IL-17 mRNA,
which suggested that skin-infiltrating T cells can produce IL-17.
Although there was no difference between the levels of IL-17 in the
Fold increase of gene expression in human
psoriatic lesion relative to uninvolved skin
1 10100 100010 000
0.11 101001000 10 000 0.01
Fold increase of gene expression in TPA-treated
K5.Stat3C mice skin relative to untreated skin
Figure 1. (a) Profiles of cytokines, b-defensins and S100A family
proteins in human psoriatic skin relative to contiguous non-lesional
skin. (b) Similar profiles in TPA-induced psoriasis like lesions in
K5.Stat3C mice. IL, interleukin; IFN, interferon; TGF, transform-
ing growth factor; TNF, tumor necrosis factor; TPA, 12-0-tetrade-
canoylphorbol-13-acetate. (Reproduced from Nakajima et al.,2with
? 2012 Japanese Dermatological Association
sera of patients with psoriasis and in controls, there was a correla-
tion between serum levels of IL-17 and the severity of psoriasis.20
These findings indicate that IL-17 may be produced in psoriatic
lesions. We showed that human psoriatic skin has elevated IL-17
gene expression in the lesions relative to uninvolved skin.2We also
revealed the infiltrating Th17 cells in the TPA-induced psoriasis-like
lesions in K5.Stat3C mice (Fig. 3). However, the specific contribu-
tion of IL-17A to the pathogenesis of psoriasis is not well under-
stood. It has been demonstrated that the i.d. injection of IL-23
elevates IL-17A expression in mouse skin, but that pretreatment
with an anti-IL-17A antibody does not ameliorate the formation of
psoriatic lesions.21This observation suggests that IL-17A is not
required for IL-23-dependent epidermal hyperplasia. However, we
demonstrated a less dominant role for IL-17A in the development
of skin lesions in K5.Stat3C mice through experiments using treat-
ment with an anti-IL-17A antibody and IL-17A-deficient mice.2
Whereas anti-IL-12⁄23p40 and anti-IL-23p19 antibodies almost
completely inhibit TPA-induced psoriasis-like lesions in K5.Stat3C
mice, the therapeutic effects of anti-IL-17A antibody or IL-17A gene
deficiency are less effective. IL-22 gene expression within skin
lesions is not affected by anti-IL-17A treatment, suggesting a lim-
ited contribution of IL-17A to epidermal hyperplasia. Our data
suggest that the development of psoriasis-like lesions is dependent
on IL-23, but is only partially dependent on IL-17A alone in our
Interleukin-17A may also function as a potent pro-inflammatory
cytokine that stimulates keratinocytes to produce neutrophil-
attracting CXC chemokines, including CXCL1, CXCL5 and CXCL
8.22Those chemokines facilitate neutrophil infiltrates into the
lesions, which indirectly impact keratinocyte proliferation. We have
shown that pretreatment with an anti-IL-17A activity decreases the
number of neutrophilic abscesses in TPA-induced psoriasis-like
lesions in the K5.Stat3C model mice.2This result supports a role for
IL-17A in the recruitment of neutrophils in psoriatic lesions. Previous
studies showed that the s.c. injection of recombinant IL-17A, IL-22
or TNF-a leads to the upregulation of both CCL20 and CCR6
expression in skin as well as in cutaneous T-cell infiltrations, sug-
gesting that Th17 cytokines stimulate CCL20 production and that
CC6+Th17 cells maintain their continued presence in psoriatic
lesions through a positive chemotactic feedback loop.23On the
other hand, IL-17 induces IL-6 and IL-8 production and enhances
the surface expression of intracellular adhesion molecule-1 in fibro-
blasts.24IL-6 is one of the important cytokines involved in Th17 dif-
ferentiation. Therefore, IL-17 may play a role in forming the direct
and⁄or indirect feedback loop in both the epidermis and the dermis
of psoriatic lesions.
Control lgG anti-p40anti-p19anti-IL-17A
Figure 2. Effect of antibody treatment on the development of TPA-induced psoriasis-like lesions on the backs of K5.Stat3C mice. (a) Represen-
tative macroscopic and histological views (scale bar, 200 lm). (b) Epidermal thickness of the dorsal skin. Mean thickness ± standard
deviation (micrometers). Ig, immunoglobulin; IL, interleukin; TPA, 12-0-tetradecanoylphorbol-13-acetate. **<0.01 Mann–Whitney test.
? 2012 Japanese Dermatological Association
Role of IL-23⁄Th17 axis in psoriasis
ROLE OF IL-22 IN PSORIASIS
Interleukin-22 plays an essential role in maintaining the homeosta-
sis and remodeling of epithelial tissues, including epidermal kerati-
nocytes, through the regulation of innate responses.25,26Recently,
the importance of IL-22 has been highlighted in the pathogenesis
of psoriasis.8IL-22 is a key cytokine produced by Th17 cells. IL-22
mRNA expression is upregulated in psoriatic skin lesions com-
pared to normal skin, whereas IL-22 mRNA levels in peripheral
blood mononuclear cells from psoriatic patients and from normal
controls are similar.27,28Circulating IL-22 levels are significantly
higher in psoriasis patients than in normal subjects. Triggering the
IL-22 receptor induces the proliferation and migration of keratino-
cytes, but reduces their differentiation. Furthermore, studies using
either a mouse model for psoriasis or reconstituted human epider-
mis (RHE) revealed that IL-22 mediates acanthosis through the
activation of Stat3 in keratinocytes.26Although i.d. injection of IL-23
induces psoriasis-like lesions in the ear skin of normal control mice,
it does not induce psoriasis-like lesions in IL-22 knockout mice.8
IL-20 subfamily cytokines, including IL-19, IL-20, IL-22 and IL-24,
induce Stat3 activation in keratinocytes and elicit acanthosis in
RHE.29These cytokines also induce the expression of the psoria-
sis-associated protein S100A7 and keratin 16 in RHE and cause
persistent Stat3 activation in keratinocytes. Interestingly, IL-22 has
the most pronounced effects on keratinocyte proliferation and it
also alters keratinocyte differentiation that leads to the attenua-
tion of the granular cell layer (hypogranulosis). The sum of these
findings indicates that IL-22 may have an essential function down-
stream of IL-23 in the pathogenesis of psoriasis. We also demon-
strated that transcriptional levels of IL-22 are upregulated in human
psoriatic lesions and in TPA-induced psoriasis-like lesions in
K5.Stat3C mice.2We showed that IL-22-producing cells are
increased not only in CD3+but also in CD3)populations in skin
draining lymph node cells of Stat3C mice following the i.d. injection
of IL-23 or topical TPA treatment. A striking observation was that
staining of CD56 in the CD3)cell population reveals that natural
killer (NK)-22 cells (CD56+IL-22+) are increased by IL-23 stimula-
tion, whereas CD56)IL-22+cells remain unchanged. It has been
demonstrated that cells expressing NK cell markers and NK-T-cell
markers are present in the papillary dermis in plaques of psoria-
sis.30Moreover, NK cells are recruited in psoriatic skin through the
CXCL10⁄CXCR3 and the CCL5⁄CCR5 axes.31These chemokines
may contribute to the amplification and chronic course of psoriasis.
Most recently, it has been shown that IL-22 produced by NK cells
may play an important role in immune defense and tissue protec-
tion.32Further evaluation is required to determine if NK-22 cells are
involved in human psoriasis.
A recent study showed that approximately 40% of IL-22-produc-
ing Th cells in psoriasis are Th17 cells and that the majority of IL-22-
producing cells do not secrete IL-17 or IFN-c.33These exclusively
IL-22-producing Th cells, termed Th22 cells, coexpress CCR6 and
the skin-homing receptors CCR4 and CCR10.34,35They respond to
the elevated CCL20 levels in psoriatic skin. It has also been demon-
strated that CD11c+dermal DC stimulate Th17 activation, whereas
epidermal Langerhans cells facilitate Th22 responses.36
We have recently demonstrated that topical application of a
small molecule Stat3 inhibitor, STA-21 (ochronomycinone), results
in the clinical amelioration of psoriatic lesions not only in K5.Stat3C
mice and but also in human psoriasis.37We have also shown that
STA-21 suppresses the proliferation of human keratinocytes in vitro
and upregulates keratinocyte differentiation-related molecules,
including Keratin 1, involucrin and transglutaminase 1. These data
indicate that Stat3 signaling in the epidermis is critical for psoriasis
development through the over-proliferation and altered differentia-
tion of epidermal keratinocytes.
LOOP BETWEEN INNATE IMMUNITY AND
LL-37, an antimicrobial peptide released by keratinocytes, forms
complexes with self-DNA from damaged cells, and stimulates plas-
macytoid DC (pDC) through triggering Toll-like receptor (TLR)9 to
release IFN-a.38In addition, LL-37 might form complexes with self-
RNA to stimulate pDC, as well as myeloid DC (mDC), which leads to
the release of the inflammatory cytokines TNF-a, IL-6 and possibly
IL-23. Furthermore, mDC activation through self-RNA-LL-37 com-
plexes promotes the maturation of DC that enhances antigen-pre-
for endogenous antimicrobial peptides in breaking innate tolerance
to self-DNA⁄RNA, leading to the autoimmune response in psoriasis.
In fact,psoriasispatientstreatedwith atopicalTLR7 agonist, imiqui-
mod, which activates pDC to secrete large amounts of IFN-a, had
exacerbation of their psoriatic lesions.39Moreover, IFN-a produced
Figure 3. Infiltration of T-helper (Th)17 cells in the dermis of K5.Stat3C mice. Immunostaining of the ear skin of K5.Stat3C mice after short-term
TPA treatment demonstrated Th17 cells (triangles in bottom panel), which were probed by Alexa Fluor 488 for CD4 (upper panel) and by Alexa
Fluor 594 for IL-17A (middle panel). Arrows, CD4+cells other than Th17; *, IL-17-producing cells other than Th17 (some of them were positive for
CD8 (Tc17), data not shown; dotted line, epidermis–dermis border (scale bar, 50 lm). IL, interleukin; Th, T-helper cell; 12-0-tetradecanoylphor-
? 2012 Japanese Dermatological Association
DC (Tip-DC), by which the IL-23⁄Th17 pathway is activated. Thus,
peptides derived from keratinocytes play a role in the positive
We showed that transcriptional levels of b-defensin 2, b-defensin
3 and S100A family members, such as S100A7 (psoriasin), S100A8
and S100A9, are upregulated in psoriatic lesions as previously
reported.2Moreover, similar findings were demonstrated in psoria-
sis-like lesions in K5.Stat3C mice.2The activation of the IL-23⁄Th17
pathway in psoriasis confers the overproduction of these antimicro-
bial peptides, which may contribute to the positive feedback
involved in the pathogenesis of psoriasis.
In vitro studies have shown that IL-22 synergizes with IL-17A and
IL-17F to enhance the keratinocyte expression of antimicrobial pep-
tides.7,40IL-17A, IL-17F and IL-22 have been shown to induce
keratinocytes to express b-defensin 2, b-defensin 3, lipocalin and
S100 proteins. Alternatively, genetic polymorphisms in DEFB4,
which encodes b-defensin 2, may also contribute to antimicrobial
resistance.40,41The expression of another antimicrobial peptide,
cathelicidin, can also be enhanced by IL-17 in the presence of vita-
min D3.42These proteins may function as key inflammation
inducers that protect against infections upon disruption of the epi-
dermal barrier. Further, IL-22 can also drive the epithelial cell release
of chemokines, such as IL-8, a key factor for neutrophil recruitment
into psoriatic lesions.40Upregulation of antimicrobial peptides and
the accumulation of neutrophils may induce epidermal hyperplasia
in psoriasis. From all these findings, we suggest that psoriatic
lesions may show an ‘‘over-defense for infection’’ that might be one
aspect of the pathogenesis of psoriasis. From these data, the con-
cept emerges that IL-17A and IL-22 are key mediators of cutaneous
inflammation, linking Th17 pathology with epithelial pathology, and
thus contributing to the pathogenesis of psoriasis.
Advances in genetics and immunology have demonstrated the rele-
vance of the immune pathway to the pathogenesis of psoriasis. A
large amount of clinical and experimental data have established
Th17 cells as the key players and have provided an exciting
advance in our understanding of the pathogenesis of psoriasis. Our
study using K5.Stat3C mice demonstrated that IL-23 is the relevant
upstream cytokine that is required for proliferation or maturation of
Th17 cells and other cells to generate a psoriatic phenotype of the
epidermis. Future investigations will further clarify the role of the
IL-23⁄Th17 axis and their interplay with other relevant cellular and
molecular pathways of the innate and adaptive immune systems in
The author thanks Prof. Shigetoshi Sano (Kochi University) for
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