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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.
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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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