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Seon Hee Chang and Chen Dong
A novel heterodimeric cytokine consisting of IL-17 and
IL-17F regulates inflammatory responses
Seon Hee Chang1, Chen Dong1
1Department of Immunology, MD Anderson Cancer Center, 7455 Fannin, Unit 906, Houston, TX 77030, USA
CD4+ helper T (TH) cells play crucial roles in immune responses. Recently a novel subset of TH cells, termed THIL-17,
TH17 or inflammatory TH (THi), has been identified as critical mediators of tissue inflammation. These cells produce
IL-17 (also called IL-17A) and IL-17F, two most homologous cytokines sharing similar regulations. Here we report
that when overexpressed in 293T cells, IL-17 and IL-17F form not only homodimers but also heterodimers, which we
name as IL-17A/F. Fully differentiated mouse THi cells also naturally secrete IL-17A/F as well as IL-17 and IL-17F
homodimeric cytokines. Recombinant IL-17A/F protein exhibits intermediate levels of potency in inducing IL-6 and
KC (CXCL1) as compared to homodimeric cytokines. IL-17A/F regulation of IL-6 and KC expression is dependent on
IL-17RA and TRAF6. Thus, IL-17A/F cytokine represents another mechanism whereby T cells regulate inflammatory
responses and may serve as a novel target for treating various immune-mediated diseases.
Keywords: inflammation, IL-17, T cells
Cell Research (2007) 17:435-440. doi: 10.1038/cr.2007.35; published online 24 April 2007
Correspondence: Chen Dong
Tel: +1-713-563-3203; Fax: +1-713-563-0604
Received 13 March 2007; revised 25 March 2007; accepted 25 March 2007;
published online 24 April 2007
IL-17 is the founding member of a new cytokine fam-
ily that includes 5 additional molecules, IL-17B, IL-17C,
IL-17D, IL-17E (also known as IL-25) and IL-17F [1,
2]. IL-17 expression has been previously associated with
many inflammatory diseases in humans, such as rheuma-
toid arthritis, multiple sclerosis, asthma, systemic lupus
erythematosus and allograft rejection. In vitro, IL-17
regulates inflammatory responses by inducing the expres-
sion of IL-6, Groα, GM-CSF, several chemokines (CCL2,
CCL7, CXCL1, and CCL20) and matrix metalloproteinases
(MMP3 and MMP13) [1,3]. Moreover, IL-17 and TNFα
exhibit synergy in promoting inflammatory gene expression
. Deficiencies in IL-17 signaling result in impaired host
defense against microbacterial infections  and resistance
to autoimmune diseases [3, 6-8].
IL-17 binds to and signals through IL-17 receptor A
(IL-17RA), a member of the IL-17R family . Recently,
it was reported that IL-17RA might form a heterodimer
with IL-17RC . IL-17 activates NFkB and MAP kinase
pathways, which results in the up-regulation of IL-6 [11,
12]. It was shown that IL-6 induction by IL-17 in mouse
embryonic fibroblasts (MEF) is dependent on TRAF6
Recent efforts to identify the source of IL-17 have re-
vealed a new lineage of T helper (TH) cells, called THIL-17,
TH17 or inflammatory TH (THi). Originally found to be
regulated by ICOS costimulatory receptor and IL-23 cy-
tokine in vivo [2, 13], IL-6 and TGFβ have been recently
shown to initiate THi differentiation in vitro [14-16], in
which IL-23 plays a synergistic role .
In addition to IL-17, differentiated THi cells also
produce IL-17F upon activation . IL-17F shares the
strongest homology with IL-17 and the two genes located
in the same chromosome region . A recent study dem-
onstrated coordinated regulation of IL-17 and IL-17F gene
transcription during THi differentiation, possibly through
chromatin remodeling at this locus . Expression of
IL-17F has also been linked with human inflammatory
Cell Research (2007) 17:435-440.
© 2007 IBCB, SIBS, CAS All rights reserved 1001-0602/07 $ 30.00
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diseases, including asthma . Treatment of human air-
way epithelial cells, vein endothelial cells, and fibroblasts
with IL-17F induced the expression of IL-6, IL-8, GROα,
ENA-78, transforming growth factor-β (TGF-β), MCP-1
(Monocyte chemotactic protein-1, CCL2), G-CSF, granu-
locyte-macrophage colony-stimulating factor (GM-CSF)
and intercellular adhesion molecule-1 (ICAM-1) [19-23].
Although the receptor of IL-17F is yet to be identified, it
at least in part may utilize IL-17RA .
In the current study, we found that IL-17 and IL-17F,
when overexpressed in vitro or derived from mouse THi
cells, form not only homodimers but also a heterodimer,
IL-17A/F. IL-17A/F, on its own or in synergy with TNFα,
regulates the expression of IL-6 and KC (CXCL1, murine
homolog of human Groα), which is dependent on IL-17RA
Materials and Methods
Analysis of 293T cells expressing IL-17 and/or IL-17F
IL-17 and IL-17F cDNA were PCR-amplified and cloned into the
pcDNA 3.1+ expression vector (Invitrogen) followed by sequencing
confirmation. 293T cells were transfected with the pcDNA-IL-17,
IL-17F or empty vector by calcium phosphate transfection. After 2
d of culture, supernatants from 293T cells expressing IL-17, IL-17F
or both were collected. Supernatants were resolved on 10% SDS-
PAGE and blotted with a rat anti-IL-17 antibody (BD PharMingen)
and a polyclonal rabbit anti-mouse IL-17F antibody we generated
(to be described elsewhere). Specific binding was visualized by Su-
per Signal substrate (Pierce) and quantified by using an EpiChemi3
DarkroomTM (UVP Bioimaging Systems). For immunoprecipita-
tion, 5 ml of supernatant culture was incubated with 1µg of IL-17
antibody or 1 µg of affinity-purified IL-17F polyclonal antibody for
4 h at 4 °C. 20 µl of Protein G or Protein A-agarose beads (Sigma)
were added to immunoprecipitation mixtures for 2 h at 4 °C. Beads
were washed 3 times with PBS and the bound complexes were eluted
with SDS-sample buffer.
Purification of recombinant cytokines
Flag and His tags were added to IL-17 or IL-17F cDNAs, re-
spectively, at the carboxyl terminus using PCR and the resulting
constructs were evaluated by sequencing and western blot. Homodi-
mers were purified using Flag or His tag affinity columns. To purify
heterodimeric protein, supernatants from 293T cells expressing
both Flag-tagged IL-17 and His-tagged IL-17F were first applied
to His tag affinity column. His-tagged IL-17F was eluted with 250
mM Imidazole and applied to Flag affinity column. Eluants were
dialyzed with PBS and analyzed by western blotting before being
used for in vitro stimulation of peritoneal macrophages and mouse
embryonic fibroblasts (MEF). Single chain of IL-17A/F heterodimer
was generated by using a PCR strategy as described before .
His-tagged IL-17F was fused via a (Gly4Ser)3 linker peptide to the
carboxy-terminal end of IL-17 and this molecule was designated as
CD4+ T cells from OT-II mice were differentiated into THi cells
as previously described . 5 d after activation, THi cells were
washed twice before restimulation with 500 ng/ml ionomycin and
50 ng/ml PMA overnight. 5ml of supernatants were applied for im-
munoprecipitation as described above.
IL-17RA–/– mice were provided by Amgen (Seattle, Washington)
and bred in MD Anderson Cancer Center animal facility. Mouse
macrophages were obtained from peritoneal lavage of mice 4 d after
injection with 4% thioglycollate broth (Difco). After culturing for
3 h, non-adherent cells were removed, and adherent macrophages
were used for experiments.
MEF were derived from C57BL6 using a standard protocol.
TRAF6-/- MEF were provided by Dr Tak Mak (Toronto, Canada).
MyD88-/- MEF were provided by Dr Ruslan Medzhitov (Yale Uni-
versity, New Haven). For measurement of IL-6 or KC production,
4×104 cells were plated onto 24-well plates. Next day, cells were
treated with various cytokines overnight, and the culture supernatants
were then analyzed by ELISA.
IL-17 and IL-17F form a heterodimer
In order to test the specificity of our polyclonal anti-
IL-17F antibody in western blotting, we expressed IL-17
and/or IL-17F in 293T cells and immunoblotted the culture
supernatants with an anti-IL-17 or anti-IL-17F antibody. As
expected, anti-IL-17 only detected secreted proteins from
IL-17-expressing cells while anti-IL-17F only detected
those from cells expressing IL-17F (Figure 1A). IL-17
migrated as 2 bands between 26 and 37 kDa on a non-reduc-
ing gel, indicating homodimer formation and differential
glycosylations. On the other hand, IL-17F migrated above
37 kDa as 2 bands. Interestingly, when IL-17 and IL-17F
were co-expressed, molecular weights of detected proteins
in non-reducing SDS-PAGE gel were different compared
with IL-17 or IL-17F expressed alone. Anti-IL-17 detected
a higher molecular weight band close to 37 kDa and anti-
IL-17F revealed a lower molecular weight band at less than
37 kDa (Figure 1A). This observation suggests a possibility
of protein complexes distinct from simple IL-17 and IL-
To determine whether IL-17 and IL-17F form a heterodi-
mer, culture supernatants from 293T cells overexpressing
IL-17 and IL-17F were used for immunoprecipitation.
First, anti-IL-17 antibody was used to precipitate any IL-
17-containing complexes. Precipitates were blotted with
anti-IL-17F, and 2 bands were identified (Figure 1B).
Similarly, immunoprecipitation of culture supernatants
with anti-IL-17F antibody also pulled down IL-17, which
confirmed the existence of a heterocomplex. Under reducing
conditions, these proteins migrated between 17 and 21 kDa
as monomers, consistent with previously reported molecular
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Seon Hee Chang and Chen Dong
weight of IL-17  or IL-17F . Thus in addition to ho-
modimers, IL-17 and IL-17F also form a heterodimer when
overexpressed in 293T cells.
To assess whether THi cells, which co-express IL-17 and
IL-17F, also produce heterodimers containing IL-17 and
IL-17F, differentiated mouse THi cells were re-stimulated
with PMA and Ionomycin overnight and the supernatants
were subjected to immunoprecipitation as described above.
Anti-IL-17 antibody precipitated 3 forms of IL-17, 2 of
which were recognized by anti-IL-17F antibody (Figure
1C). Likewise, anti-IL-17F antibody immunoprecipitated
3 forms of IL-17F and at least one of these forms was rec-
ognized by the anti-IL-17 antibody. Interestingly, in these
experiments, the species that were immunoprecipitated by
either anti-IL-17 or anti-IL-17F but showed reactivity with
the other antibody, were found to migrate at the same posi-
tion in non-reducing gel (Figure 1C). Densitometric quan-
tification of the western blot indicated that approximately
22.7 % of anti-IL-17 immunoprecipitants were detected by
anti-IL-17F antibody and 30.8 % of anti-IL-17F immuno-
precipitants were detected by anti-IL-17 antibody.
Thus, IL-17 and IL-17F form a heterodimeric complex
not only when they are co-expressed in transfected cells but
also as physiologically secreted products from T cells. We
name this novel cytokine molecule IL-17A/F hereafter.
Biological activity of IL-17A/F heterodimer
To assess the biological activity of the IL-17A/F heterodi-
mer, IL-17 and IL-17F cDNAs were cloned with Flag and
His tags at the C-terminus, respectively. The two cytokine
homodimers were purified using affinity columns. Purity and
identity of the isolated recombinant proteins were confirmed
with Commassie blue staining (data not shown) and western
blot (Figure 2A). IL-17A/F heterodimer was purified by
two-step affinity purification. First, culture supernatants of
293T cells were applied to a His tag affinity column, and
Figure 1 IL-17 forms a heterodimeric complex with IL-17F. (A) Western blot of IL-17 and IL-17F from culture supernatants of
293T cells. 48 h after transfection, culture supernatants of 293T cells transfected with indicated expression vectors were collected
and resolved on non-reducing SDS-PAGE gels and subject to blotting with anti-IL-17 or IL-17F antibody. (B) culture supernatants
from 293T cells expressing IL-17, IL-17F or both were immunoprecipitated (IP) with anti-IL-17 or anti-IL17F antibody and the elu-
ants were applied to reducing SDS-PAGE and immunoblotting (IB) with anti-IL-17 or anti-IL17F antibody. (C) Differentiated THi
cells were restimulated with PMA and ionomycin overnight. Supernatants were immunoprecipitated with anti-IL-17 or anti-IL-17F
antibody and the eluants were analyzed by immunoblotting.
IP: αIL17 IP: αIL17F
IL17 IL17F IL17F
IB: αIL17 αIL17F αIL17F αIL17
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then the eluants were added to a Flag tag affinity column.
Identity of the IL-17Flag/FHis heterodimer was confirmed by
western blotting with anti-IL-17 and anti-IL-17F antibod-
ies (Figure 2A).
We next compared the activities of IL-17, IL-17F and
IL-17A/F proteins prepared in this manner. IL-17 and
IL-17F are known to target fibroblast, epithelial cells and
macrophages to produce IL-6 and KC. When mouse em-
bryonic fibroblasts (MEF) were treated with different doses
of recombinant cytokines, IL-17 was most potent in induc-
ing IL-6 and KC (Figure 2B). IL-17A/F heterodimer has
intermediate activity between IL-17 and IL-17F. However,
at >100 ng/ml concentrations, the ability of these cytokines
to induce IL-6 or KC expression was indistinguishable.
We also generated a single chain of IL-17A/F protein,
in which IL-17 was fused with IL-17F via a linker. The re-
sulting protein was purified via His tag affinity column and
named as IL-17A-L-F. Similar to IL-17Flag/FHis, recombinant
IL-17A-L-F was able to synergize with TNFα to induce the
KC production by wild-type macrophages (Figure 3A).
Our results thus demonstrate that recombinant IL-17A/F
proteins are biologically active and regulate pro-inflamma-
Signaling requirements of the IL-17A/F heterodimer
IL-17 mediates inflammatory responses dependent on
IL-17RA and TRAF6. To understand the receptor usage of
IL-17A/F, peritoneal macrophages from wild-type and IL-
17RA-deficient mice were isolated. Upon treatment with
IL-17, IL-17Flag/FHis or IL-17A-L-F, there was no induction of
KC or IL-6 in wild-type or knockout cells. However, similar
to IL-17, recombinant IL-17A/F proteins synergized with
TNFα to increase KC expression (Figure 3A). Increase of
KC expression by IL-17, IL-17Flag/FHis or IL-17A-L-F was
impaired in the absence of IL-17RA (Figure 3A), indicating
IL-17A/F also utilizes IL-17RA as its receptor.
We also tested the involvement of TRAF6, a signaling
molecule that associates with IL-17RA and Act1 adaptor
protein . While KC or IL-6 induction by IL-17Flag/FHis or
IL-17A-L-F was preserved in MyD88-/- MEF, their produc-
tion was abolished in TRAF6 KO MEF (Figure 3B).
While THi cells secret IL-17 and IL-17F upon activa-
tion, we found that an additional cytokine, consisting of
heterodimeric IL-17A/F, is also produced by THi cells.
0 0.001 0.01 0.1 1 10 100
0 0.01 0.1 1 10 100 1000
Concentration of cytokines (ng/ml)
IL17Flag IL17FHis IL17Flag/FHis
Flag His His
IB: IL17 IL17F
IL 6 ng/ml
Figure 2 Regulation of inflammatory responses by IL-17A/F. (A) Preparation of recombinant cytokines. Supernatants of 293T cells
expressing Flag-tagged IL-17 were applied to a Flag affinity column to purify IL-17 homodimers. His-tagged homodimeric IL-17F
was purified using a His-tag affinity column. IL-17Flag/FHis heterodimer was purified by a His affinity column followed by a Flag af-
finity column. Purified proteins were run on SDS-PAGE and immunoblotted with anti-IL-17 or anti-IL-17F antibody. (B) MEF were
treated with indicated cytokines overnight and culture supernatants were measured for KC and IL-6 levels by ELISA.
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Seon Hee Chang and Chen Dong
Medium IL17Flag/FHis IL17A-L-F
Recombinant IL-17A/F functions very similarly as its
homodimeric counterparts. It targets fibroblasts or macro-
phages to induce pro-inflammatory molecules such as IL-6
and KC. Our study thus suggests that IL-17 and IL-17F
promote inflammation in the forms of homodimers and
Identification of the IL-17A/F heterodimer may reveal
further complexity in receptor usage by IL-17 cytokines in
promoting inflammatory responses. While it is generally
accepted that IL-17 utilizes IL-17RA for its signaling and
IL-17RA forms complex with IL-17RC, the receptor for
IL-17F is not clear. It has been suggested that IL-17F may
use the same receptor, IL-17RA, although with different
affinity since IL-17F did not bind to IL-17RA in vitro. Our
study revealed that IL-17A/F also requires IL-17RA for its
signaling. Although it is likely that all of these cytokine
molecules act in concert to create a pro-inflammatory
environment, one cannot exclude the possibility that these
molecules may compete for the binding to IL-17RA or
other receptors in vivo.
So far, the IL-17A/F heterodimer did not exhibit any
unique biological property compared with its homodimeric
counterparts. However, the role of IL-17A/F in vivo should
be examined more thoroughly, for instance, by overexpres-
sion in mice. Also, development of blocking antibodies
or antagonistic peptides that react with the IL-17A/F het-
erodimer in addition to respective homodimers would be
more appropriate to inhibit inflammatory responses driven
by the IL-17 family.
THi cells now are recognized as a distinct lineage of CD4
helper T cells that produce heterogeneous combinations
of inflammatory molecules. It was demonstrated recently
that IL-22, a pro-inflammatory molecule, is also derived
from THi cells and synergizes with IL-17 and IL-17F to
induce the production of antimicrobial peptides [26, 28].
Therefore, identification of the IL-17A/F heterodimer, em-
phasizes the inflammatory role of THi cells in vivo. Future
studies should be considered to determine the effect of the
IL-17A/F heterodimer in cooperation with its homodimeric
counterparts and other pro-inflammatory cytokines on
development and progression of human diseases.
In conclusion, we found that THi cells upon stimulation
produce not only IL-17 and IL-17F homodimers but also the
IL-17A/F heterodimer. Similar to homodimers, IL-17A/F
activates fibroblasts and macrophages to produce pro-
inflammatory mediators such as KC and IL-6. IL-17A/F
signals through IL-17RA and TRAF6. These results reveal
a novel mechanism whereby T cells regulate inflammatory
Figure 3 IL-17A/F signals through IL-17RA and TRAF6. (A) WT and IL-17RA KO peritoneal macrophages were treated with IL-17,
IL-17Flag/FHis and IL-17A-L-F in the absence or presence of TNFα. 24 h after treatment, KC was measured from culture supernatants
by ELISA. Asterisk indicates statistically significant differences as determined by two-tailed Student’s test (P<0.05). (B) Indicated
MEF were treated with IL-17Flag/FHis and IL-17A-L-F overnight and the culture supernatants were measured for KC and IL-6 levels
(Asterisk indicates P<0.05).
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responses. Considering the similar actions of IL-17, IL-17F
and IL-17A/F, it may be beneficial to target all of them in
many inflammatory diseases that now have been found to
be mediated by THi cells.
We thank Dr Ruslan Medzhitov (Yale University) for
MyD88-deficient MEF, Dr Tak Mak (Toronto, Canada)
for TRAF6-deficient MEF, Amgen (Seattle) for IL-17RA
KO mice and the entire Dong Lab for help and discussion.
This work was in part supported by National Institutes of
Health (to Dong C). Chang SH receives a post-doctoral
fellowship from the Arthritis foundation and Dong C is a
Cancer Research Institute Investigator, an American Lung
Association Career Investigator and a MD Anderson Cancer
Center Trust Fellow.
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