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Cytokine Network in Psoriasis
IL-1RL2 and Its Ligands Contribute to the
Jennifer E. Towne and John E. Sims
Bhagavathula, Muhammad Nadeem Aslam, James Varani,
Trueblood, Keith Bailey, Donna Shows, Narasimharao
Hal Blumberg, Huyen Dinh, Charles Dean, Jr., Esther S.
2010; 185:4354-4362; Prepublished online 10
, 24 of which you can access for free at:
cites 63 articles
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The Journal of Immunology
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The Journal of Immunology
IL-1RL2 and Its Ligands Contribute to the Cytokine Network
Hal Blumberg,*,1Huyen Dinh,* Charles Dean, Jr.,* Esther S. Trueblood,*
Keith Bailey,* Donna Shows,* Narasimharao Bhagavathula,†Muhammad Nadeem Aslam,†
James Varani,†Jennifer E. Towne,* and John E. Sims*
Psoriasis is a common immune-mediated disease in European populations; it is characterized by inflammation and altered
epidermal differentiation leading to redness and scaling. T cells are thought to be the main driver, but there is also evidence
for an epidermal contribution. In this article, we show that treatment of mouse skin overexpressing the IL-1 family member,
IL-1F6, with phorbol ester leads to an inflammatory condition with macroscopic and histological similarities to human psoriasis.
Inflammatory cytokines thought to be important in psoriasis, such as TNF-a, IL-17A, and IL-23, are upregulated in the mouse
skin. These cytokines are induced by and can induce IL-1F6 and related IL-1 family cytokines. Inhibition of TNF or IL-23 inhibits
the increased epidermal thickness, inflammation, and cytokine production. Blockade of IL-1F6 receptor also resolves the in-
flammatory changes in human psoriatic lesional skin transplanted onto immunodeficient mice. These data suggest a role for IL-1F
family members in psoriasis. The Journal of Immunology, 2010, 185: 4354–4362.
increase in and dilation of superficial dermal blood vessels (1). The
disease involves patches of lesional skin separated from each other
by normal-appearing skin. T cells have been implicated as key
players in psoriasis by the finding that agents affecting T cell sur-
vival, activation, or function demonstrate clinical efficacy (1, 2).
Psoriasis has been difficult to model in the mouse because of
profound differences in the structure and development of mouse
and human skin (3, 4). The most widely accepted models involve
transplantation of human skin from psoriasis patients onto immu-
nodeficient mice (5, 6). Transplanted lesional skin retains its pso-
riatic characteristics, but it can be normalized by agents that are
clinically effective in humans (4). Transplanted nonlesional skin
from psoriasis patients can be converted to the psoriatic phenotype
by the patient’s own activated T cells, but skin from normal indi-
viduals treated in the same way cannot, suggesting an abnormality
in the skin in addition to the altered function of T cells from
patients (5–7). Genetic and ex vivo studies also provide support
for a role of keratinocytes in disease (8–13).
hyperproliferation and altered differentiation, an inflam-
matory cell infiltrate in the epidermis and dermis, and an
Psoriasis appears to involve a cytokine network centered around
IL-17, IL-22, IL-23, and TNF, all of which are elevated in lesional
skin (14–17). IL-22 (along with its related cytokines IL-19, IL-20,
and IL-24) was shown to cause epidermal hyperplasia, primarily by
downregulation of genes involved in terminal keratinocyte differ-
that lead to neutrophil, inflammatory dendritic cell (TNF/iNOS-
the skin (21). IL-17 and IL-22 induce keratinocytes to produce
against infection and act as endogenous ligands for TLRs, such as
TLR4 and TLR9 expressed on keratinocytes and dendritic cells
(DCs) (25, 26). Human b-defensin 2 is also chemotactic for CCR6+
cells (27), which include neutrophils, DCs, and Th17 cells, and for
CCR2+cells (28), which include TIP-DCs. IL-23 enhances the
production of IL-17 and IL-22 from Th17 and other cells (29, 30).
TIP-DCs make inducible NO synthase (leading to NO, which can
35). TNF amplifies many of these responses, further activating DC
populations in the skin and inducing cytokines, such as IL-1, IL-6,
and IL-8, from keratinocytes and fibroblasts to promote continued
Th17 differentiation and neutrophil recruitment. Neutrophils, in
turn, can cause tissue damage via reactive oxygen species and pro-
teases, which exposes self-Ags and generates endogenous TLR
ligands. TLR stimulation of skin-resident DCs causes IL-12 syn-
generation of CXCR3 chemokines that recruit more T cells to the
lesion (36). There may be a role for IFN-a in maturation of DCs,
particularly at plaque initiation (6). Known triggers for psoriasis
include trauma and infection, resulting in generation of exogenous
or endogenous TLR ligands and other pathogen-associated and
damage-associated molecular patterns, which may provide entry
points into the cycle of mutually reinforcing gene expression
and cell-recruitment loops described above.
The IL-1 family contains 11 members (37, 38). IL-1a, IL-1b,
IL-18 and IL-33 all have known roles as agonists affecting inflam-
mation and/or adaptive immunity, whereas IL-1ra acts to inhibit
*Amgen, Seattle, WA 98119; and†Department of Pathology, University of Michigan
Medical School, Ann Arbor, MI 48109
1Current address: Department of Cellular Immunology, Novo Nordisk Inflammation
Research Center, Seattle, WA.
Received for publication January 29, 2010. Accepted for publication July 15, 2010.
This work was supported by Amgen and by Grant AR052889 from the U.S. Public
Health Service (to J.V.).
Address correspondence and reprint requests to Dr. Hal Blumberg or Dr. John Sims,
Department of Cellular Immunology, Novo Nordisk Inflammation Research Center,
530 Fairview Avenue North, Seattle, WA 98109-5507 (H.B.) or Amgen, 1201 Amgen
Court West, Seattle, WA 98119 (J.E.S). E-mail addresses: email@example.com
(H.B.) or firstname.lastname@example.org (J.E.S.)
The online version of this article contains supplemental material.
Abbreviations used in this paper: CT, cycle threshold; DC, dendritic cell; IHC, im-
munohistochemistry; Tg, transgenic; TIP-DC, TNF/iNOS-producing dendritic cell;
TLDA, TaqMan low density array; TPA, 12-O-tetradecanoylphorbol-13-acetate.
by guest on June 18, 2013
IL-1a and IL-1b action. IL-1F6, -1F8, and -1F9 are agonists of
the IL-1R family member IL-1RL2 (also known as IL-1R rp2) (39,
40). IL-1F5 serves to antagonize these responses in a manner par-
alleltothatusedbyIL-1raforIL-1 responses(39)(J.E.Towne, B.R.
Renshaw, J. Douangpanya, B.P. Lipsky, M. Shen, C.A. Gabel, J.E.
Sims, unpublished data). Global-expression analysis of IL-1 family
members demonstrated that IL-1F6, -1F8, and -1F9 were highly
these, the most abundant expression was in skin. We surveyed a va-
riety of human inflammatory skin conditions and found that IL-1F6,
-1F8, and -1F9 were upregulated in psoriatic lesions (44) (H. Blum-
berg, H. Dinh, D. Shows, and J.E. Sims, unpublished data). Micro-
array studies of psoriatic skin also found upregulation of IL-1F9 (45).
We previously reported that transgenic overexpression of IL-1F6
under control of the keratin-14 promoter leads to an inflammatory
er ofinflammatory cytokines andchemokines are upregulated inthe
inflamed skin, and TNF inhibition leads to a decrease in epidermal
thickness. In this article, we demonstrate that application of an ir-
ritant can rapidly induce psoriatic-like skin inflammation in phe-
notypically normal skin from 2–3-mo-old transgenic mice. We
characterize the skin changes and cytokine involvement in much
more detail than in our previous publication. We show that cyto-
kines, such as IL-17, IL-22, and IL-23, known to be involved in
human psoriasis, are overexpressed in this model and that they can
induce IL-1F6, which, in turn, can induce IL-17, IL-22, and IL-23,
thus establishing a self-amplifying gene-expression loop. We also
provide a direct link to human psoriasis by demonstrating that
agents approved for clinical treatment of psoriasis are beneficial in
this model, as well as by showing that inhibition of the IL-1F6 re-
ceptor IL-1RL2 ameliorates the lesional phenotype in human pso-
riatic skin. The results presented in this article greatly strengthen
the connection between IL-1RL2 ligands and human psoriasis.
Materials and Methods
Transgenic mice (44) were backcrossed at least eight times to C57BL/6 or
FVB mice (both from Taconic Farms, Oxnard, CA). Male mice on the
C57BL/6 background were further bred to female rag22/2mice (B6.129S6-
Rag2tm1FwaN12; Taconic Farms), and backcrosses between those progeny
were performed to create B6. 3 rag22/2mice. Animal studies were con-
ducted under protocols approved by the Institutional Animal Care and Use
Committee at Amgen.
Fc (etanercept) and a comparable protein made from murine IgG1 and mu-
rine TNFRp75 were from Amgen. Anti–IL-23p19 mAb 16E5 (generated at
Amgen) and the widely used anti–IL-12/23p40 mAb clone C17.8 were con-
verted to a murine IgG1 isotype. 16E5 and C17.8 inhibit IL-23 induction of
IL-17 in a murine splenocyte assay with comparable potency. 16E5 does not
affect IL-12 induction ofIFN-g in mouse splenocytes,whereastheC17.8Ab
antagonizes IL-12 activity with comparable potency to its antagonism of IL-
23. Murine IL-1F6 used for injection was an N-terminal truncation mutant
beginning at aminoacid arginine 8. This version has considerably greater sp.
act. than full-length murine IL-1F6 (J.E. Towne, B.R. Renshaw, J. Douang-
panya, B.P. Lipsky, M. Shen, C.A. Gabel, J.E. Sims, unpublished data). The
same is true of the murine IL-1F9 variant used, which begins at glycine 13.
Both were made at Amgen. Murine IL-23 was from Amgen, whereasmurine
IL-17A, IL-22, TNF, and IFN-g were purchased from R&D Systems (Min-
12-O-tetradecanoylphorbol-13-acetate treatment protocol
FVB transgenic 8–12-wk-old male mice (generated at Amgen) had their
dorsal hair shaved 24 h prior to 12-O-tetradecanoylphorbol-13-acetate
(TPA) administration. On days 0 and 4, mice (other than the naive control
group) received 12.5 mg TPA (Sigma-Aldrich, St. Louis MO) in 200 ml
acetone by topical administration to the shaved back. At 4 or 48 h (day 6)
after the second TPA injection, photos were taken for gross observation,
and full-thickness back skin was excised and divided into three sections:
lower back skin was saved in formalin for histopathology, midback skin
was processed for RNA, and upper back skin (collected using an 8-mm
biopsy punch to obtain a fixed area) was snap-frozen in liquid nitrogen for
protein analysis. Abs and soluble TNFRp75-Fc (500 mg each) were in-
jected i.p. on days 21 and 3.
Eight- to nine-week old male FVB mice (Taconic Farms) were injected
intradermally into back skin on 2 consecutive days (two injections; short
protocol) or every other day for 12 d (six injections; long protocol) with 500
ng each cytokine or PBS. Four hours after the final injection, full-thickness
skin around the injection site was harvested for RNA isolation.
RNA isolation, cDNA synthesis, and quantitative PCR
Total skin RNAwas extracted using the RNeasy Mini kit (Qiagen, Valencia,
cDNA Reverse Transcription Kits (Applied Biosystems, Foster City, CA),
according to the manufacturers’ directions. Quantitative RT-PCR was done
using a customized TaqMan low density array (TLDA) plate with 62 query
genes and 2 control genes (HPRT and 18S rRNA). Genes not on the TLDA
platewereanalyzedusingAssay-on-Demandprimerand probe sets(Applied
Biosystems). Assay numbers (Mm00439307_m1, Mm00446231_m1, Mm-
01220132_g1, Mm00656925_m1, Mm00438270_m1, Mm0044228_m1,
Mm99999114_s1, Mm00438285_m1, Mm00731768_m1, Mm00806979_m1,
Mm00445341_m1, Mm00519250_m1, Mm01219775_m1, Mm0043919-
1_m1, and Mm01281447_m1) used were as follows: HB-EGF, TGF-a,
S100A8, S100A9, CCR2, CCL20, CCR6, CAMP, BDEF4, BDEF14, IL-20,
IL-1RL2, STAT3, granzyme A, and VEGF, respectively.
Multianalyte profiling-analysis protocol and details
Full-thickness skin samples from each group were collected with 8-mm
biopsy punches and homogenized in 1.6 ml cell lysis buffer (Cell Signaling
Technology, Beverly, MA) containing one protease inhibitor tablet EDTA-
free (Roche, Indianapolis, IN). Aliquots of the lysates (250 ml) were sent to
Rules-Based Medicine (Austin, TX) for multianalyte profiling. Additional
ELISAs were run for IL-17F, IL-20, and IL-22 using specific duo kit
ELISAs (R&D Systems).
Skin transplantation and treatment protocol
Replicate 6-mm punch biopsies of full-thickness plaque skin were obtained
from human skin donors with psoriasis. Sun-protected skin from nonpsoriatic
Michigan Institutional Review Board. All subjects provided written informed
consent prior to biopsy. SCID mice (CB-17 strain; Taconic Farms) were used
as tissue recipients. One piece of tissue from each normal or psoriatic volun-
teer was transplanted onto the dorsal surface of a recipient mouse as follows.
This tissue was secured to the back of the mouse with absorbable sutures (4-0
Dexon “S”, Davis-Geck, Manati, Puerto Rico). The transplant was bandaged
with Xeroform petrolatum dressing (Kendall, Mansfield, MA) for 5 d. The
animals were maintainedina pathogen-free environmentthroughoutthe prep-
aration and treatment phases. Treatment was initiated 1–2 wk posttrans-
plantation, depending on the healing rate of the transplanted tissue. Animals
with the human skin transplants were divided into treatment groups (isotype
control Ab, anti–IL-1RL2 Ab, or etanercept as a positive control). Animals
were treated with seven injections each of 150 mg anti-human IL-1RL2,
isotype matched control Ab, or etanercept i.p. on alternate days. All proce-
dures involving animals were approved by the University of Michigan
Committee on Use and Care of Animals. At the end of the treatment phase,
animals were photographed and then euthanized. The transplanted human
tissue along with the surrounding mouse skin was surgically removed and
fixed in 10% formalin. After embedding the tissue in paraffin, multiple 5-mm
onto microscope slides, and stained with H&E.
For cytokeratin 6 and CD3 immunohistochemistry (IHC), skin samples were
fixed in 10% neutral buffered formalin and embedded in paraffin. Depar-
affinized tissue sections were subjected to Ag retrieval using Citra solution
(no. HK086-9K; BioGenex, San Ramon, CA) in a Decloaking Chamber
of the cytokeratin 6 Ab (no. PRB-169P; Covance, Berkeley, CA) or with
The Journal of Immunology4355
by guest on June 18, 2013
60 min. Detection was performed with an anti-rabbit Mach 3 Rabbit AP
Polymer Kit (nos. RP531L & RAP533L; Biocare), followed by Permanent
Red chromogen solution (no. K0640; Dako North America, Carpinteria,
CA). For the CD11c IHC, skin samples were frozen in OCT Compound (no.
4583; Sakura, Torrance, CA). Tissue sections were incubated with a 1:100
dilution of a biotinylated CD11c Ab (no. 553800; BD Biosciences, Phar-
mingen, San Diego, CA) at room temperature for 60 min. Detection was
performed with streptavidin-alkaline phosphatase (no. NEL750; Perkin-
Elmer, Waltham, MA) with tyramide signal amplification (no. SAT700B;
PerkinElmer), followed by Permanent Red solution. For the CD31 IHC, skin
samples were fixed in IHC zinc fixative (no. 550523; BD Biosciences,
Pharmingen) and embedded in paraffin. Deparaffinized tissue sections were
incubated with a 1:30 dilution of CD31 Ab (no. 533370; BD Biosciences
Pharmingen) for 60 min at room temperature. Detection was performed with
a Vectastain ABC-AP kit (no. AK-5000; Vector Laboratories, Burlingame,
CA), followed by Permanent Red solution. Following the IHC-staining
procedure, slides were counterstained with hematoxylin (no. S3309; Dako
North America), dehydrated, cleared, and coverslipped. To quantify changes
in the number of CD3+and CD11c+cells and the area of CD31+vessels in
response to TPA treatment, five representative digital images of each IHC
assay from each individual animal were analyzed using MetaVue mor-
phometry software (version 6.2r6; Universal Imaging, Downingtown, PA).
The CD3 and CD11c images were taken with an 320 microscope objective
(3200 magnification) and are expressed as the number of positive cells per
mm2. The CD31 images were taken with an 340 microscope objective
(3400 magnification) and are expressed as the CD31+area in mm2/mm2of
We previously reported that transgenic overexpression of IL-1F6
in mouse skin results in a hyperproliferative, inflammatory skin
condition in newborn animals that resolves by 3 wk of age only to
reappear at ∼6 mo (44). Resolution could be prevented and the
phenotype exacerbated by eliminating one copy of the IL-1F5 an-
appearance of the skin of K14/F6 transgenic
(Tg) mice treated with TPA. Mice were
treated with TPA, acetone vehicle, or noth-
ing on days 0 and 4, and skin was harvested
on day 6. A, Gross appearance of skin from
wild-type or transgenic mice on the FVB
background. B, H&E staining of skin. C,
IHC for the endothelial cell marker CD31.
D, IHC for cytokeratin 6, a marker of
proliferating keratinocytes. E, IHC for the
T cell marker CD3. F, IHC for the DC
marker CD11c. G, Gross appearance and
H&E staining of skin from rag2+/+and
rag22/2transgenic mice on the C57/BL6
background treated with TPA. H, Gross
appearance and H&E staining of skin from
wild-type or transgenic mice on the FVB
background, treated with TPA, in the pres-
ence of an anti–IL-1RL2 Ab or an isotype-
matched control Ab. Scale bar, 0.04 mm
in B and D; 0.02 mm in all other panels. A
and B are representative of nine different
experiments; G represents four experiments;
H represents two experiments. The IHC
results in C–F are from one experiment with
at least three mice in each group, all of
which showed similar features. Original mag-
nification of B and D 3100; C, E, F, G, and
Macroscopic and histological
4356IL-1 FAMILY MEMBERS IN PSORIASIS
by guest on June 18, 2013
tagonist gene (44). We have now found that treatment of transgenic
mouse skin with TPA at a time when it is phenotypically normal
(∼2–3 mo of age) elicits skin inflammation to a much greater extent
than TPA treatment of nontransgenic skin (Fig. 1A, 1B, Supple-
mental Fig. 1A). The morphology of TPA-treated transgenic skin
is similar to lesional skin of human psoriasis. Macroscopically,
the skin appears reddened, thickened, scaly, and crusted (Fig 1A).
Histologically, there is epidermal hyperplasia (acanthosis); a thick-
ened stratum corneum (hyperkeratosis) containing nucleated cells
(parakeratosis); neutrophilic microabscesses in the stratum spino-
sum and the stratum corneum; a mixed dermal infiltrate containing
macrophages/DCs, neutrophils, and lymphocytes; and an increase
in and dilation of superficial dermal blood vessels (as evidenced by
CD31 staining, which is increased 6-fold in TPA-treated transgenic
mice compared with 1.8-fold in TPA-treated wild-type mice) (Fig.
1B, 1C, Supplemental Fig. 1A, 1B, 1D). A granular layer (normally
difficult to see in mouse skin) becomes prominent in the hyper-
treated transgenic mice, particularly in areas of more severe lesion.
Although the most obvious epidermal penetrations into the dermis
are associated with hair follicles, there is more unevenness to the
lower margin of the epidermis than is typical for mouse, suggestive
of rete ridges found in psoriatic skin. Cytokeratin 6, indicative of
proliferating keratinocytes, is expressed throughout the epidermis
(Fig. 1D) in wild-type and transgenic mice in response to TPA.
However, it is noteworthy that even in apparently normal untreated
transgenic mice, cytokeratin 6 staining reveals focal patches of
mildly proliferative skin (Fig. 1D, Supplemental Fig. 1C), sug-
gesting that the transgenic skin is poised on the brink of abnormal
proliferative changes. These focal proliferative patches are not seen
in wild-type mice. CD3+T cells are also increased in the epidermis
after TPA treatment in transgenic and wild-type mice (2.3-fold and
1.8-fold, respectively) (Fig. 1E, Supplemental Fig. 1D). There is
a significant increase in CD11c+DCs, especially in the upper layers
of the dermis (9.7-fold in transgenic mice, 2.7-fold in wild-type
mice after TPA treatment) (Fig. 1F, Supplemental Fig. 1D). An
ment with TPA, is typical of psoriasis (46). Although the general
presentation is similar to that of human psoriatic skin, there are also
points of difference. The most obvious of these is the role of
T lymphocytes.Diseaseintransgenic mice occurson a lymphocyte-
deficient rag22/2background (Fig. 1G), suggesting that T cells are
not required, whereas T lymphocytes are believed to play a key role
in human psoriasis. Other differences include the variable presence
or loss of a granular-appearing layer beneath the stratum corneum,
the relative paucity of lymphocytes in the infiltrate in the mouse
disease, and the uncertain presence of rete ridges. Elicitation of skin
hyperplasia and inflammation by TPA is dependent on the IL-1F6
transgene, because it can be prevented by injection of an anti–IL-
1RL2 neutralizing mAb (Fig. 1H). These findings made us wonder
whether IL-1F6, -1F8, and/or -1F9 might account for part of the
epidermal contribution to human psoriasis.
To probe the similarity between human psoriasis and skin in-
flammation caused by overexpression of IL-1F6, we examined the
expression of a number of genes relevant to skin or inflammation
by quantitative PCR. Skin samples were taken from nontransgenic
and K14/F6 transgenic mice, either untreated or treated with TPA.
Genes substantially upregulated in transgenic animals treated with
Micewere treated with TPA or acetonevehicle on days 0 and 4 or were not treated (naive), and RNAwas prepared from full-thickness skin sections harvested
HPRT. The normalized values for selected genes are shown. Each data point represents one mouse. The figure is representative of two experiments.
TPA treatment results in elevated expression of genes encoding cytokines and antimicrobial peptides in K14/F6 mouse skin treated with TPA.
The Journal of Immunology4357
by guest on June 18, 2013
TPA, but not in other groups, included cytokines, chemokines, and
antimicrobial peptidesthatare knowntobeupregulatedinpsoriasis
(Fig. 2, Supplemental Table 1). These include IL-17A, IL-22, IL-
23 (both p19 and p40 subunits), and the antimicrobial peptides
S100A8, S100A9, and b-defensin 4 (the ortholog of human b-
defensin 2). IL-1b, a regulator of Th17 differentiation, was also
upregulated, as were IL-19, IL-20, and IL-24, cytokines related to
IL-22 and possessing similar activities. TNF-a was upregulated by
TPA in transgenic and nontransgenic mice.
Mutual induction of inflammatory cytokines and IL-1
To establish directly whether IL-1F6 is capable of inducing genes
implicated in psoriasis pathology, we injected IL-1F6 intrader-
mally into wild-type mice and analyzed transcript levels in skin
for selected genes (Fig. 3A, Supplemental Table 2). IL-1F6 led
to substantial increases in IL-17A, IL-23, TNF, and IFN-g
mRNA. IL-1F6 also strongly induced itself, as well as other IL-1
family members, chemokines, growth factors, and antimicrobial
We next asked whether cytokines known to be elevated in
psoriatic skin could induce IL-1F6 and other family members.
TNF, IL-17A, IL-23, and IFN-g were able to induce IL-1F6 mRNA
following intradermal injection of cytokines into wild-type mice
(Fig. 3B, Supplemental Table 3, data not shown). Induction was
usually stronger when combinations of these cytokines, as well as
IL-22, were used (Supplemental Table 3). Some of these cytokines
also induced IL-1F8 and IL-1F9 (Supplemental Table 3). Thus,
a positive feedback loop may exist in psoriatic skin, with cytokines,
such as IL-17, IL-22, IL-23, and TNF, inducing IL-1F6 and IL-
1F9, which, in turn, amplify expression of the previously impli-
cated inflammatory cytokines as well as themselves.
Response to therapeutics
TNF inhibitors are effective in treating psoriasis (47) and are ap-
proved for this purpose in many countries. Abs that block the action
of IL-12 and IL-23 have proven successful in clinical trials (48),
and one is approved for treating psoriasis in the European Union,
Canada, and the United States. Human-expression data and genetic-
susceptibility studies suggest that Abs inhibiting the action of IL-23
alone would be effective as well (16, 49, 50). Because the mor-
phologic appearance of and gene-expression patterns in the skin of
K14/F6 transgenic mice treated with TPA were similar to those of
human psoriatic skin, we asked whether agents known or suspected
to be efficacious in treating psoriasis would have therapeutic effects
in the mice. K14/F6 transgenic mice were treated with candidate
agents on days 21 and 3 and with TPA at days 0 and 4. Mouse skin
was evaluated macroscopically and histologically at day 6, and
samples were taken for mRNA and protein analysis at 48 h after the
second TPA application. Therapeutic agents examined were soluble
TNFRp75-Fc, an anti–IL-12/23p40 Ab, and an anti–IL-23p19 Ab.
Mice treated with any of these agents showed a markedly improved
appearance of the skin (Fig. 4). The skin was also improved histo-
logically, with reduced acanthosis, hyperkeratosis, parakeratosis,
inflammatory cell infiltrate, dilation of dermal capillaries, and loss
of granular layer compared with skin from mice treated with
isotype-matched control Abs (Fig. 4). Moreover, gene-expression
studies (Fig. 5, Supplemental Table 4) and protein analyses (Sup-
plemental Table 5) showed reductions in mRNA for IL-17A and
-17F, IL-22, IL-1b, chemokines, and antimicrobial peptides after
treatment, as well as reductions in protein levels for most of these
as well (IL-17A protein was below the level of detection for the
assay used, and protein levels were not analyzed for antimicrobial
proteins). For all of these features, inhibition of IL-12/23p40 or
IL-23p19 was more effective than TNF inhibition, although the
cessive days or using six injections over 12 d, as described in Materials and Methods. RNA was prepared from full-thickness skin sections harvested 4 h
after the last injection. TaqMan quantitative PCR was performed, and the CT value for each gene was normalized to that for HPRT. The normalized values
for selected genes are shown. Each data point represents one mouse. A, Induction of selected genes by IL-1F6. B, Induction of IL-1F6 by inflammatory
cytokines. There was no induction of IL-1F6 by IL-17A or IFN-g when used alone. The figure is representative of four experiments.
IL-1F6 is a component of a cytokine network. Wild-type FVB mice were injected intradermally with cytokines or with PBS on two suc-
4358IL-1 FAMILY MEMBERS IN PSORIASIS
by guest on June 18, 2013
effectiveness of TNF inhibition varied from modest to excellent
in different experiments. These results indicate that the psoriasis-
like pathology in the skin of TPA-treated transgenic mice is re-
sponsive to the same therapeutic approaches used effectively for
IL-1RL2 in human psoriatic skin
Mouse and human skin are quite different. Therefore, many inves-
tigators have studied psoriasis preclinically by transplanting skin
from psoriasis patients onto immunodeficient mice (5, 6). Technical
treated with TPA to induce skin inflammation and were given antagonists of TNF (TNFRp75-Fc), IL-12/23p40, or IL-23p19 or isotype control Ab, as
described in Materials and Methods. The photographs show the macroscopic appearance of the skin, as well as skin sections stained with H&E, taken 2
d after the second TPA application. Treatment with anti–IL-12/23p40 or anti–IL-23p19 led to reduction in acanthosis, hyperkeratosis, and parakeratosis, as
well as to loss of the granular cell layer, inflammatory infiltrate, and dermal blood vessel prominence. Rare intracorneal pustules are still present in mice
treated with anti–IL-23p19 or anti–IL-12/23p40 (data not shown) Ab. Treatment with TNFRp75-Fc led overall to less severe disease than in the control
mice, but parakeratosis, loss of the granular cell layer, and intracorneal and intraepidermal pustules persist in some areas. The figure is representative of
three experiments. Scale bar, 0.02 mm. Original magnification 3200.
Skin pathology in K14/F6 mice treated with TPA is ameliorated by inhibitors of TNF, IL-12/23p40, and IL-23p19. Transgenic mice were
mouse skin treated with TPA. Transgenic mice were treated with TPA to induce skin inflammation and were given antagonists of TNF (TNFRp75-Fc), IL-
12/23p40, or IL-23p19 or isotype-matched control Ab, as described in Materials and Methods. RNA was prepared from full-thickness skin sections
harvested 48 h after the second TPA treatment. TaqMan quantitative PCR was performed, and the CT value for each gene was normalized to that for HPRT.
The normalized values for selected genes are shown. Each data point represents one mouse. The figure is representative of two experiments for anti-TNF
and anti-p40 treatment and of six experiments for anti–IL-23p19 treatment.
Inhibition of TNF, IL-12/23p40, or IL-23p19 results in decreased expression of cytokines, antimicrobial peptides, and chemokines in K14/F6
The Journal of Immunology4359
by guest on June 18, 2013
model unsuitable for biochemical studies, but it has been very in-
formative when analysis is focused on efficacy as defined by histo-
logical parameters, such as epidermal thickness. Agents that are ef-
fective at treating psoriasis normalize the appearance of lesional
lesional skin transplanted onto SCID mice with an isotype control
Ab or an Ab to the human IL-1RL2 receptor to block the action of
IL-1F6, -1F8, and -1F9. As can be seen in Fig. 6, anti–IL-1RL2
substantially reduced the epidermal hyperplasia and other skin
changes associated with psoriasis. In one experiment, we obtained
enough tissue to also use etanercept as a positive control; the effects
with etanercept were comparable to those seen with anti–IL-1RL2.
The anti-human IL-1RL2 Ab does not cross-react with mouse
IL-1RL2, and mouse IL-1F6 (or IL-1F8 or IL-1F9) does not signal
through human IL-1RL2 (data not shown). Therefore, human IL-
1F6, -1F8, and/or -1F9 are important for maintaining the psoriatic
phenotype in the transplanted human skin in this model.
much of the focus in the last decade has been on the role played
by cells of the hematopoietic system, as well as their products, in
driving the disease (1, 2). The contribution made by psoriatic skin
to the disease has been less well explored. The evidence presented
in this article suggests that IL-1F6, -1F8, or -1F9, acting through
the IL-1RL2 receptor, may represent one important way in which
keratinocytes contribute to psoriasis. We found that TLR3 ligands
and inflammatory cytokines are able to induce IL-1 family mem-
bers from human keratinocytes (H. Dinh, U. Martin, C.A. Gabel,
J.E. Sims, unpublished data). Polymorphisms in the epidermal-
differentiation complex on human chromosome 1 are associated
with susceptibility to psoriasis (8, 12, 13), and it is possible that
altered barrier function in skin allows microbial, osmotic, or other
stimulators of keratinocytes to lead to production of IL-1F6, -1F8,
of many genes capable of driving the phenotypic characteristics of
psoriatic skin (IL-17, IL-22, IL-23, TNF-a) or of recruiting and
maintaining the required cell populations (chemokines and anti-
microbial proteins). The induced inflammatory cytokines are also
The biggest difference between the skin inflammation in this
the mouse disease on T cells. T cells are thought to be central to
psoriasis pathogenesis, and cytokines that act on (IL-23, IL-12, and
TNF) or are made by (IL-17, IL-22, TNF, and IFN-g) T cells play
important roles in disease. Although T cells are not required for the
mouse skin inflammation, we have not investigated whether the
disease mechanisms and gene-expression profiles are the same in
wild-type versus rag2 knockout animals. In the wild-type back-
ground, at least, the IL-1F6 transgenically expressed in keratino-
cytes likely acts inanautocrinefashion on keratinocytes themselves
as well as on skin DCs and macrophages; all of these cell types
express the receptor protein IL-1RL2 (J.E. Sims et al., unpublished
data). IL-1F6 may enhance synthesis of cytokines, chemokines, and
antimicrobial proteins from keratinocytes and TNF, IL-20, and
IL-23 from TIP-DCs (Fig. 3A, Supplemental Table 2). IL-1F6 can
less potently) (D. Swart and J. Tocker, personal communication),
leading to increased IL-17 production (Fig. 3A, Supplemental Table
point to that provided by activated T cells for the upregulation of
T cells, itis not knownwhether other cytokines,such asTNF, IL-20,
and IL-24, and IL-1F proteins can substitute for the key functions of
made by other, non-rag2–dependent cell types. It is notable that
mast cells can make IL-17 (53), that neutrophils contribute IL-17
during Leishmania infection (54), and that NK cells and DCs can
express IL-22 (55, 56). In addition, IL-17 is induced, and IL-23 is
The mechanism by which TPA induces disease in K14/F6mice is
notunderstood.Although IL-1F6 mRNAexpressionis considerably
higher in TPA-treated transgenic skin than it is in TPA-treated wild-
type skin (Supplemental Tables 1, 6), it is induced only 3.5-fold by
TPA inthetransgenic skin,andtheF5:F6 antagonist:agonistmRNA
ratio is reduced by only 2-fold after TPA induction in the transgenic
mouse (Supplemental Table 6). Changes in expression of other IL-1
family genes after TPA treatment are comparably modest. These
phenotypethat followsTPA treatment oftransgenic mouseskin.We
recently found that the sp. act. of IL-1F6 is increased ∼10,000-fold
by proteolytic processing near the N terminus (J.E. Towne, B.R.
Renshaw, J. Douangpanya, B.P. Lipsky, M. Shen, C.A. Gabel, J.E.
Sims, unpublished data). TPA is known to induce expression of a
large number of genes in mouse skin (Supplemental Table 1) (1),
more of these cell types or their products might be important to
complement the action of IL-1F6 in setting up the self-amplifying
gene-expression loop. In this scenario, the preconditioning of the
K14F6 transgenic mouse skin to perturbation by TPA would be
skin to respond to trauma in the well-known Koebner reaction.
Transgenic overexpression or knockout of other IL-1 family
but none show the many points of similarity to human psoriasis that
are seen with overexpression of IL-1F6. Skin conditions resembling
psoriasis to varying extents have also been created by manipulation
of a number of other genes in mice (3, 4, 63). However, mouse
models are perhaps less successful at reconstructing human disease
than they are at allowing exploration of genes and pathways plau-
sibly relevant to human conditions. TPA-treated K14/F6 transgenic
mice develop a skin inflammation characterized by increased ex-
pression of many genes characteristic of human psoriasis, which is
ameliorated by agents known towork clinically in psoriasis patients
(TNF and IL-12/23p40 inhibitors). Amelioration by an anti–IL-
23p19 Ab suggests that IL-23, rather than IL-12, is the dominant
p40-containing cytokine involved in the mouse disease. Ligands for
IL-1RL2 are also critical for maintaining the psoriatic character-
istics of human lesional skin, at least when transplanted onto
pathology in a human psoriatic skin xenogeneic model. Plaque skin from
psoriasis patients was transplanted onto the backs of SCID mice, as de-
scribed in Materials and Methods. After 1–2 wk to allow the grafts to heal,
the micewere treated every other day for 2 wk with the anti–IL-1RL2 Ab or
an isotype-matched control Ab. Etanercept was used as a positive control in
the experiment shown. Representative histology images of H&E stained
skin sections are shown from four patients transplanted onto at least two
mice for each patient. Original magnification 3200.
4360 IL-1 FAMILY MEMBERS IN PSORIASIS
by guest on June 18, 2013
immunodeficient mice. The data presented in this article suggest
that agents that block signaling through IL-1RL2 could be useful
therapeutically in psoriasis.
We thank Blair Renshaw for providing IL-1F cytokines, Hiko Kohno for
murine TNFRp75-Fc protein, Brian Lipsky for help with TLDA gene pro-
filing, Kathy Rohrbach for help with IHC, Jacques Peschon for useful dis-
cussions, Eva Gonzalez-Suarez for advice on TPA treatment of mouse skin,
Guang Chen for help with analysis of gene-expression data, and Dirk Smith
for comments on the manuscript.
H.D., C.D., E.S.T., K.B., D.S., J.E.T., and J.E.S. are employees of Amgen
and own Amgen stock and/or stock options. H.B. was an employee of
Amgen during part of the time that this work was done and owns Amgen
stock. N.B., N.D.A., and J.V. have no financial conflicts of interest.
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