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14 Exacerbates Collagen-Induced Arthritis
Overexpression of CXC Chemokine Ligand
Marinova, Pumin Zhang, Biao Zheng and Shuhua Han
Limo Chen, Linjie Guo, Jun Tian, Hongxia He, Ekaterina
2010; 184:4455-4459; Prepublished online 8
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The Journal of Immunology
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The Journal of Immunology
Overexpression of CXC Chemokine Ligand 14 Exacerbates
Limo Chen,*,1Linjie Guo,*,1Jun Tian,*,1Hongxia He,* Ekaterina Marinova,*
Pumin Zhang,†Biao Zheng,* and Shuhua Han*
CXCL14 is a relatively new chemokine with unidentified receptor and undefined function. Recently, we found that CXCL14 is
upregulated in arthritic joints in a mouse model of autoimmune arthritis, collagen-induced arthritis. To examine the role of
CXCL14 in the development and pathogenesis of autoimmune arthritis, we have generated transgenic (Tg) mice that overexpress
CXCL14 under control of phosphoglycerate kinase promoter. The results showed that CXCL14-Tg mice developed more severe
arthritis compared with wild-type controls. The draining lymph nodes of CXCL14-Tg mice were significantly enlarged and con-
tained an increased number of activated T cells, particularly the CD44+CD62Lloweffector memory cells. In addition, T cells from
CXCL14-Tg mice exhibited an enhanced proliferative response against collagen II and produced higher levels of IFN-g but not
IL-4 or IL-17. CXCL14-Tg mice also had elevated levels of IgG2a autoantibodies. These findings indicated that CXCL14 plays an
important role in the autoimmune arthritis, which may have an implication in understanding the pathogenic mechanisms of
rheumatoid arthritis in humans and, ultimately, therapeutic interference.
pressed in epithelium (1–3). Although CXCL14 is abundantly
expressed in normal tissues, it is absent in many tumor cell lines,
and its expression in human cancers is heterogeneous, with many
cancers losing CXCL14 expression (1). The receptor selectivity
of CXCL14 is still unknown, and its function also remains largely
unclear. Several reports indicate a role of CXCL14 in antitumor
immunity (4–6). It has also been reported that CXCL14 may be
involved in the generation of tissue macrophages and act as
a chemotactic factor for immature dendritic cells (DCs) (6–8).
However, the role of CXCL14 in inflammatory responses is not
Recently, in search of genes that are predominately expressed
during the development of collagen-induced arthritis (CIA), we
the inflammatory disease. To study the function of CXCL14 and its
role in inflammation, we have generated transgenic (Tg) mice that
promoter. We found that CXCL14-Tg mice developed more severe
CIA compared with wild-type controls. Moreover, CXCL14-Tg
increased activation of autoreactive T cells, augmented type 1 cy-
tokine production, and elevated levels of autoantibodies. These re-
sults indicate for the first time that CXCL14 plays a role in the
The Journal of Immunology, 2010, 184: 4455–4459.
XCL14 (breast and kidney-expressed chemokine) is
a CXC chemokine constitutively expressed in normal
tissues, such as breast and kidney, and predominantly ex-
development and pathogenesis of autoimmune arthritis, implying
a novel pathway for therapeutic intervention in the autoimmune
Materials and Methods
Generation of CXCL14 Tg mouse lines
Mouse CXCL14 cDNA containing 39 flag tag (agcgcagggtctacgaagaa) was
amplified by PCR using specific primers (59-CACGAATTCCCAGCAT-
GAGGCTC-CTGGCGGCCGC-39) and (59-GGAGAATTCTCACTTAT-
with C57BL/6 cDNA as template. The fragment was digested with EcoRI
and inserted into the kbpa vector downstream of PGK promoter. The DNA
fragment was gel purified, linearized, and microinjected into the pronucleus
of fertilized eggs of C57BL/6 mice (Transgenic Mouse Facility at Baylor
Collegeof Medicine, Houston,TX). Thefollowingtwo sets ofprimerswere
used to detect CXCL14 transgene in tail DNA: 59-CACGAATTCCCAG-
CATGAGGCTCCTGGCGGCCGC-39 and 59-GGAGAATTCTCACTTAT-
CGTCGTCATCCTTGTAATC-39; and 59-GAATTCGACTAGAGCTCGC-
TGATCAGCCTCGACTG-39 and 59-GATTCGAGGCTAGAACTAGTGG-
ATCT-CGAGCCCCA-39. The mice were housed in autoclaved micro-
isolators, provided with sterile bedding, food, and water, and maintained on
a 12-h day/night cycle. Animal experimentation was performed in accor-
dance with protocols approved by the Animal Research Committee of
Baylor College of Medicine.
CXCL14 expression by ELISA and real-time PCR
Five mice from each group were used to measure CXCL14 expression by
ELISA. Briefly, the tissue lysates were prepared by homogenization in lysis
buffer (50 mM Tris-HCl [pH 7.4], 1% Triton X-100, 0.2% sodium deoxy-
cholate, 1 mM sodium ethylene diamine tetraacetate, and 1 mM phenyl-
methylsulfonyl fluoride). Tissue and cell debris were removed by centrifu-
gation at 10,000 rpm for 5 min. Protein concentration was determined with
a spectrophotometer. ELISA plates were coated with 10 mg/ml monoclonal
organs of wild-type and CXCL14-Tg mice were diluted to 0.3 mg/ml of
protein concentration and added into the plates. Biotin-conjugated poly-
clonal anti-mouse CXCL14 (R&D Systems, Minneapolis, MN) was used as
the detecting Ab.
CXCL14 expression was also assessed by real-time PCR.Total RNAwas
isolated from various tissues of wild-type and CXCL14-Tg mice as pre-
viously described (9). The sequences for primers and probe were: forward,
59-GGCCCAAGATCCGCTACA-39; reverse, 59-TGGGTACTTTGGCTT-
CATTTCC-39; probe, 59-CGACGTGAAGAAGC-39. Real-time PCR was
carried out using ABI prism 7700 (Applied Biosystems, Foster City, CA).
*Department of Immunology and†Department of Molecular Physiology and Bio-
physics, Baylor College of Medicine, Houston, TX 77030
1L.C., L.G., and J.T. contributed equally to this work.
Received for publication February 18, 2009. Accepted for publication February 7,
Address correspondence and reprint requests to Dr. Shuhua Han, Department of
Immunology, Baylor College of Medicine, One Baylor Plaza, M929, Houston, TX
77030. E-mail address: firstname.lastname@example.org
Abbreviations used in this paper: CIA, collagen-induced arthritis; CII, collagen II;
DC, dendritic cell; PGK, phosphoglycerate kinase; Tg, transgenic.
by guest on June 13, 2013
Induction of CIA and evaluation of arthritis
Wild-type and CXCL14-Tg mice on C57BL/6 background (8–12 wk old,
both sexes) were immunized as previously described (10, 11). Briefly, mice
were injected intradermally at the base of the tail with 100 mg (in 100 ml)
chicken collagen II (CII) (Sigma-Aldrich) dissolved in 0.01 M acetic acid
and emulsified in an equal volume of CFA prepared by grinding 100 mg
heat-killed Mycobacterium tuberculosis (H37Ra; Difco Laboratories, De-
troit, MI) in 20 ml IFA (Sigma-Aldrich). Three weeks after primary im-
munization, mice were given the same injection. Mice were observed for
the onset of arthritis, and an arthritis index was derived by grading the
severity of each paw as described (12). Each paw was scored based on the
degree of swelling and periarticular erythema using a scale of 0–3 as
follows: 0 = no evidence of erythema or swelling; 1 = erythema confined to
one joint region only; 2 = erythema and swelling limited to one joint region
only; and 3 = severe erythema and swelling extending from the ankle to the
midfoot (tarsal) joint, involving both joint regions. Scores from all four
paws were added to provide the total score for each mouse. The maximum
possible score per mouse was 12. The incidence was expressed as the
percentage of mice that showed visible symptoms of arthritis.
Single-cell suspensions of draining lymph nodes from wild-type and
CXCL14-Tg mice with CIAwere stained with different Abs to cell surface
markers. Abs to CD3, CD4, CD8, CD44, CD62L, B220, and CD19 were all
purchased from BD Pharmingen (San Diego, CA). The samples were ac-
quired by an FACSCalibur flow cytometer (BD Bioscience, San Jose, CA)
and analyzed using FlowJo software (Tree Star, San Carlos, CA).
Detection of anti-CII Abs by ELISA
CII-specific Abs in mouse sera were determined by ELISA as described
(11). Briefly, microplates were coated with chicken CII overnight and then
blocked with 10% FCS. Serum samples were added and incubated for 1 h
at 37˚C and followed by addition of HRP-conjugated goat anti-mouse IgM,
IgG1, and IgG2a (Southern Biotech, Birmingham, AL).
Draining lymph node cells pooled from the same group of mice were either
unstimulated or stimulated with different concentrations of chicken CII and
cultured in 24-well plates for 3 d. The supernatants were used to determine
the levels of various cytokines using ELISA kits (BD Pharmingen)
according to the manufacturer’s instructions.
Cells of draining lymph nodes were cultured in vitro with various con-
centrations of CII for 3 d and pulsed with [3H]thymidine (1 mCi/well) for
the last 18 h. Cellular proliferation was determined by [3H] incorporation.
Student t test (GraphPad Prism, GraphPad, San Diego, CA) was used to
determine the significance of differences in means. The p values less than
0.05 were considered to be statistically significant.
Generation of CXCL14-Tg mice
CXCL14 is expressed in different tissues including the joints, but
the expression pattern of CXCL14 in different cell lineages is not
we wanted to overexpress CXCL14 in all cell lineages using
a ubiquitous PGK promoter. Mouse CXCL14 cDNA containing
39 flag tag was inserted into the kbpa vector downstream of PGK
promoter. To determine the expression of the transgene, tissue ly-
sates from different organs of wild-type and CXCL14-Tg mice
were assayed by ELISA with anti-FLAG Ab-coated plates. The
results showed that there was significant expression of CXCL14-
FLAG in all of the tissues from CXCL14-Tg mice, but the fusion
protein was not detected in the tissues of wild-type mice (Fig. 1A).
To further examine the overexpression of CXCL14 in the Tg mice,
total RNA was extracted from different tissues of CXCL14-Tg
mice and wild-type controls and subjected to real-time PCR assay.
The levels of CXCL14 were increased by approximately 3- to 6-
fold in different tissues tested in CXCL14-Tg mice compared
with wild-type mice (Fig. 1B), confirming an overexpression of
CXCL14 in CXCL14-Tg mice.
spleen kidney brain
ferent tissue lysates from wild-type and CXCL14-Tg mice (five mice each
group) were assayed by ELISA for the expression of CXCL14-FLAG
fusion protein. B, Real-time PCR was used to determine the expression
levels of CXCL14 in various tissues. Open bars represent wild-type mice,
and solid bars represent Tg mice. Three mice per group.
Overexpression of CXCL14 in CXCL14-Tg mice. A, Dif-
Days after second injection
5 10 1520
Days after second injection
(A) and incidence (B) of arthritis in CXCL14-Tg mice (filled symbols) or
wild-type controls (open symbols) were recorded at various time points
after secondary immunization. The incidence was expressed as the per-
centage of mice that showed visible symptoms of arthritis. Values are the
mean 6 SEM with 8–10 mice in each group. Student t test was used for
statistical analysis. Data were representative of three independent experi-
ments with similar results. pp , 0.05; ppp , 0.01; pppp , 0.001.
Exacerbation of CIA in CXCL14-Tg mice. Clinical scores
4456CXCL14 IN AUTOIMMUNE ARTHRITIS
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We analyzed lymphoid tissues for cellular composition and found
in bone marrow, thymus, spleen, and lymph nodes in unmanipulated
CXCL14-Tg mice (data not shown).
Exacerbated CIA in CXCL14-Tg mice
Because we have previously found that CXCL14 is significantly
upregulatedinthe arthritic joints of micewith CIA (9),wewanted to
investigate whether overexpression of CXCL14 affects the deve-
lopment and pathological outcome of CIA. CXCL14-Tg mice and
wild-type controls were used to induce CIA. The results showed that
CXCL14 overexpression led to an accelerated onset of the disease
and increased disease incidence (Fig. 2). By day 17 after immuni-
zation, all CXCL14-Tg mice developed CIA, whereas only 75% of
developed more severe CIA than wild-type control mice (Fig. 2A).
Thus, our results indicate that CXCL14 overexpression promotes
the development of CIA.
Increased severity of CIA in CXCL14-Tg mice is associated
with an increased T cell response
We assessed the effect of CXCL14 overexpression on T cell acti-
nodes recovered from CXCL14-Tg mice were significantly in-
with those in the control mice. Because the percentages of CD3+,
CD4+, and CD8+T cells were similar between wild-type and
CXCL14-Tg mice (data not shown), both CD4+and CD8+T cells
were proportionally increased in CXCL14-Tg mice. In addition,
flow cytometry analysis shows that the percentages of effector
memory CD4+T cells (CD44+CD62Llow) out of total CD4+T cells
were significantly increased in CXCL14-Tg mice (Fig. 3C, 3D).
Because total lymph node cell numbers were increased in the Tg
mice, the increase in the percentages of effector memory T cells
indicate a significant expansion of this population in CXCL14-Tg
mice. Although the percentages of central memory CD4+T cells
(CD44+CD62Lhigh) within CD4+T cells were similar between
T cell priming and expansion. CXCL14-Tg and wild-
type control mice with CIA were sacrificed for analy-
sis. A, Sizes of draining lymph nodes. B, Total cell
numbers of the draining lymph nodes. C, Lymph node
cells were analyzed by flow cytometry. CD3+CD4+
T cells were gated and further analyzed for CD44 and
CD62L expression. D, The percentages of CD44hi
CD62Llowcells of total CD4+T cells from wild-type
mice and CXCL14-Tg mice were compared. E,
Draining lymph node cells were restimulated with CII
and harvested 72 h later in the presence of [3H]thy-
midine for the last 18 h. F, IFN-g levels in the super-
natant after 3 d culture with CII. Values are the mean 6
SEM with triplicates. Data are representative of two
independent experiments with similar results. Open
circles indicate wild-type mice; solid circles indicate
Overexpression of CXCL14 enhances
autoantibody production in CIA mice. Serum
samples were collected at peak time of CIA and
measured for the levels of IgM (A), IgG1 (B), and
IgG2a (C) isotypes of anti-CII autoantibodies by
ELISA. Each dot represents one mouse. Student
t test was used.
CXCL14 overexpression enhances
The Journal of Immunology4457
by guest on June 13, 2013
population was also proportionally increased in CXCL14-Tg mice.
in vitro restimulation with CII. Draining lymph node cells from
CXCL14-Tg mice exhibited a significantly higher proliferative
demonstrated that enhanced T cell activation and proliferation is
present in CXCL14-Tg mice, which may drive more severe ar-
thritogenic response in these mice.
CXCL14-Tg mice exhibit enhanced Th1 cytokine production
(13–15), and Th17 cells have recently been indicated to be in-
volved in the pathogenesis of autoimmune arthritis (16, 17). To
examine whether CXCL14 overexpression affects cytokine profile,
we measured cytokine production by lymph node cells from
CXCL14-Tg mice and controls. Our results show that lymph node
cells from CXCL14-Tg animals produced significantly higher
levelsofIFN-g uponinvitrorestimulation with the immunizingAg
CII (Fig. 3F). A decrease in IFN-g production in the cultures with
higher dosages of CII was observed, which may be due to the
acidic effect of CII. There were no significant differences in the
levels of IL-4, IL-10, and IL-17 between cell cultures from
CXCL14 mice and wild-type controls (data not shown).
CXCL14 overexpression enhances autoantibody production
Because anti-CII Abs play an important role in the pathogenesis of
CIA (18, 19), we determined whether CXCL14 overexpression
affected the levels of CII-specific Abs. The serum levels of IgM,
IgG1, and IgG2a CII-specific Abs were evaluated by ELISA. Our
results showed that CXCL14-Tg mice produced higher levels of
CII-specific Abs than control mice (Fig. 4). Particularly, IgM and
IgG2a isotypes of anti-CII Abs were significantly elevated in
CXCL14-Tg mice. The increase of IgG2a Ab levels is consistent
with the elevated Th1 cytokine production in CXCL14-Tg ani-
mals, indicating a predominant Th1-mediated response (20). The
increased levels of IgM and IgG2a autoantibodies may contribute
to the increased severity of CIA in CXCL14-Tg mice.
CXCL14 expression in arthritic joints of CXCL14-Tg mice
To determine whether CXCL14 is significantly elevated in the ar-
thritic joints of the Tg mice, joint tissues were isolated and subjected
to real-time PCR. Compared to the expression levels of CXCL14 in
the joint samples from naive mice, the expression of CXCL14 in
arthritic joints in both wild-type mice and CXCL14-Tg mice were
increased by more than 20-fold (Fig. 5). Although the expression
levels of CXCL14 in the arthritic joints of CXCL14-Tg mice were
increased compared with those in the arthritic joints of wild-type
mice, the difference was not statistically significant (Fig. 5).
Until now, the function of CXCL14 was largely unknown. In the
current study, our results demonstrated that overexpression of
an exacerbated arthritic response. However, the mechanisms un-
derlying the enhanced T cell response and exacerbated arthritis in
CXCL14-Tg mice remain to be investigated. We propose several
possibilities. First, overexpression of CXCL14 may promote DC
maturation and activation, which in turn promotes T cell activation.
of DCs and may be involved in DC homing in vivo (6, 8). Although
a recentreportshowed that,usingCXCL14-deficientmice,CXCL14
is dispensable for DC function and localization within peripheral
tissues (21), it may reflect a functional redundancy. Second, it has
this process, ultimately resulting in more inflammatory cytokine
secretion. Finally, because CXCL14 is a chemokine, its over-
of DCs and macrophages, as previous studies indicated (6–8, 22).
Our data indicated that CXCL14 expression in the joint of un-
immunized CXCL14-Tg micewas significantly increased compared
with that in the joint of unimmunized wild-type mice. This increase
may play a role incellinfiltration intothe jointsattheearly initiation
phase of CIA. At the peak time of CIA, the expression levels of
CXCL14 in the joints were greatly increased compared with the
CXCL14 expression levels in the normal joints. But the differences
between the expression levels of CXCL14 in arthritic joints from
control animals and CXCL14-Tg mice were not significant. The
results suggested that the increased levels of CXCL14 expression in
the Tg mice may have more profound effects at the beginning of the
inflammatory response, leading to the elevated arthritic response in
the Tg mice.
requires thorough understanding of the underlying mechanisms, our
autoimmune arthritis. This finding may have an implication in un-
possible therapeutic interference.
The authors have no financial conflicts of interest.
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