Cytokine & Growth Factor Reviews 14 (2003) 155–174
Survey
Interleukin-17 family and IL-17 receptors
T.A. Moseley1 , D.R. Haudenschild1 , L. Rose, A.H. Reddi∗
Department of Orthopaedic Surgery, Center for Tissue Regeneration and Repair, School of Medicine,
University of California, Davis, Sacramento, CA 95817, USA
Abstract
Interleukin-17 (IL-17) is a pro-inflammatory cytokine secreted by activated T-cells. Recently discovered related molecules are forming
a family of cytokines, the IL-17 family. The prototype member of the family has been designated IL-17A. Due to recent advances in the
human genome sequencing and proteomics five additional members have been identified and cloned: IL-17B, IL-17C, IL-17D, IL-17E
and IL-17F. The cognate receptors for the IL-17 family identified thus far are: IL-17R, IL-17RH1, IL-17RL (receptor like), IL-17RD and
IL-17RE. However, the ligand specificities of many of these receptors have not been established. The IL-17 signaling system is operative in
disparate tissues such as articular cartilage, bone, meniscus, brain, hematopoietic tissue, kidney, lung, skin and intestine. Thus, the evolving
IL-17 family of ligands and receptors may play an important role in the homeostasis of tissues in health and disease beyond the immune
system. This survey reviews the biological actions of IL-17 signaling in cancers, musculoskeletal tissues, the immune system and other
tissues.
© 2003 Elsevier Science Ltd. All rights reserved.
Keywords: Interleukin-17; T-cells; Receptors; Prostate; Cartilage; Cancer
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. IL-17 family overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. IL-17 family in cartilage and arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Ex vivo modeling systems help elucidate IL-17s role in joint destruction . . . . . . . . . . . . . . . . . . .
3.2. Identification of IL-17B in articular cartilage extract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. IL-17 in cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. IL-17 in prostate cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. IL-17 signaling pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6. IL-17 biological activity in other tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Interleukin-17 (IL-17A) is a cytokine secreted exclusively
by activated T-cells. IL-17 cDNA has been isolated and
cloned from the murine hybridomas (cytotoxic T lymphocyte
antigen 8 (CTLA-8)) [1,2] and has homology to open reading frame 13 from the T lymphotropic Herpesvirus saimiri.
∗ Corresponding author. Present address: University of California, Davis,
Room 2000, Research Building I, 4635 2nd Avenue, Sacramento, CA
95817, USA. Tel.: +1-916-734-3311; fax: +1-916-734-5750.
E-mail address: ahreddi@ucdavis.edu (A.H. Reddi).
1 TAM and DRH share first authorship.
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The human IL-17A gene product is a protein of 150 amino
acids with a molecular weight of 15 kDa, and is secreted
as a disulfide linked homodimer of 30–35 kDa glycoprotein
[3].
Five related cytokines were identified, through database
searches and degenerative RT-PCR, that share 20–50% homology to IL-17. IL-17 has been designated IL-17A to
indicate that it is the founding member of the IL-17 cytokine family. The shared features of the IL-17 cytokine
family include conserved cysteines which, in IL-17F [4],
have been shown to exhibit the features of a classic cystine
knot structural motif found in bone morphogenetic proteins
1359-6101/03/$ – see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S1359-6101(03)00002-9
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T.A. Moseley et al. / Cytokine & Growth Factor Reviews 14 (2003) 155–174
(BMPs), transforming growth factor beta (TGF-), nerve
growth factor (NGF) and platelet-derived growth factor BB
(PDGF-BB) [5]. IL-17F, like IL-17A, is produced primarily
in activated T-cells. In contrast, IL-17B, IL-17C, IL-17D,
and IL-17E are expressed in a wide assortment of tissues.
Their functions partially overlap those of IL-17A, although
they have not been as thoroughly investigated.
The receptor for IL-17A (IL-17R) is a single-pass transmembrane protein of approximately 130 kDa. While the
IL-17A cytokine is expressed only by T-cells, its receptor is
expressed in all tissues examined to date. The activation of
the receptor by IL-17A generally results in the induction of
other pro-inflammatory cytokines, through the activation of
NF-B.
Four additional receptors have been identified, through
database searches, which share partial sequence homology
to IL-17R. Of these, only IL-17RH1 (also called IL-17B re-
ceptor) has been shown to bind to IL-17 cytokines, namely
IL-17B and IL-17E [7,36]. IL-17 receptor-like protein (also
called IL-17RL or IL-17RC), IL-17RD (also called SEF or
IL-17RLM) and IL-17RE have only been identified by sequence similarity to IL-17R. Many of these receptors exist
as alternatively spliced isoforms, some of which may not
contain transmembrane or cytoplasmic domains, and thereby
may be acting as soluble decoy receptors. They exhibit a
broad tissue distribution, and not much is known about their
functions or signal transduction pathways.
With the newly identified family of IL-17 cytokines and
receptors, and their expression in disparate tissues, the scope
of IL-17 cytokine activity and expression extends beyond
the T-cell immune system mediated inflammatory response.
IL-17 cytokines and their receptors thus may play an important role in the homeostasis of tissues and the progression
of disease.
Fig. 1. IL-17 cytokine family alignment: alignment of human IL-17 cytokine family members shows their common features. Darker shading and boldfaced
type represent sequence identity. The conserved cysteins are in red which may be involved in intra- and inter-chain disulfide bonds. The dendrogram
shows how these cytokines are evolutionarily related.
T.A. Moseley et al. / Cytokine & Growth Factor Reviews 14 (2003) 155–174
2. IL-17 family overview
Proteins with significant homology to IL-17 have been
identified recently with the continuing advances and accumulating information in expressed sequence tags (ESTs), genomics and proteomics databases. Some of these cytokines
have alternative names as they were originally identified in
other systems. These related proteins have been grouped and
designated IL-17A–F. Fig. 1 shows an alignment of human
IL-17 cytokines, with identical residues darkly shaded and
boldface. There are five highly conserved cysteines highlighted in red, four of which have been shown to form a cystine knot in the crystal structure of IL-17F [6]. This cystine
knot is similar to a common structural motif found in growth
factors such as BMPs, TGF-s, NGF and PDGF-BB, except
that in these other growth factors the cystine knot is formed
with six cysteines rather than four. Similar to many growth
factors, members of IL-17 family of ligands are expressed as
tightly associated dimers (IL-17B) [7] or disulfide-bonded
homodimers (IL-17F) [6].
The dendrogram shown in Fig. 1 depicts the interrelationships and the degree of similarity amongst the members
of the IL-17 cytokine family. IL-17A and IL-17F share the
highest degree of homology, being 50% identical to each
other. It is interesting to note that these also map to the same
chromosomal location, 6p12. IL-17B through E are less related, sharing only 16–30% identity at the primary sequence
level, and they each map to a different chromosome. The
accession numbers, chromosomal locations in the human
genome, and alternative names are presented in Table 1.
These cytokines are well conserved in the mouse, with
62–88% similarity between the human and mouse homologs.
Proteins with significant homology to the IL-17 receptor
have been identified using sequence similarity searches of
genome databases. These proteins share only limited similarity with each other, and do not contain conserved domains
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present in other proteins. All are single-pass transmembrane
proteins with an extracellular amino-terminus. The accession numbers, chromosomal locations in the human genome,
and alternative names are presented in Table 1. These receptors are well conserved in the mouse, with 68–90% similarity at the protein level between the human and mouse
homologs. IL-17RH1 and IL-17RD are both mapped to the
same chromosomal location, 3p21.1, as are IL-17RL and
IL-17RE which both map to 3p25.3.
The genomic structure of the IL-17 receptor family of
proteins is shown in Fig. 2. All receptors are transcribed
from multiple exons, ranging from 11 in IL-17RH1 to
19 in IL-17RL. With the notable exception of IL-17R,
there is extensive evidence of alternative splicing of these
receptors, which is diagrammed by lines connecting adjacent exons in splice variants in Fig. 2. The alternative
splicing of IL-17RH1 and IL-17RL has been shown to
create frame-shifts and introduce stop codons which result
in secreted soluble proteins [8,9]. These soluble proteins
presumably retain their ligand-binding properties, yet lack
signal transduction capability thereby acting as soluble decoy receptors. There is also evidence of alternative splicing
of IL-17RE in the EST database, although the effects on
the protein have not been documented. Alternative transcription start sites are evident in the various isoforms of
IL-17RD, which produce proteins named IL-17RLM long
and IL-17RLM short, and there are reports of an alternative
translational start site in this gene which produce a protein
named SEF [10,11].
3. IL-17 family in cartilage and arthritis
To provide a suitable context for understanding the actions
of IL-17 cytokines in cartilage and arthritis, we provide a
brief overview of cartilage function and tissue homeostasis.
Table 1
Identification of IL-17 family
Name
Ligands
IL-17A
IL-17B
IL-17C
IL-17D
IL-17E
IL-17F
Receptors
IL-17R
IL-17RH1
IL-17RL
IL-17RD
IL-17RE
Alternate
name 1
CTLA-8
CX1
CX2
IL-27
IL-25
ML-1
IL-17AR
IL-17BR
IL-17RC
SEF
Alternate
name 2
NERF
IL-27A
Evi27
IL-17RLM
Chromosome
location
Human protein
accession
number
Human mRNA
accession
number
Mouse protein
accession
number
Mouse mRNA
accession
number
Homolgy to
human (%)
6p12
5q32
16q24
13q11
14q11.1
6p12
NP
NP
NP
NP
NP
NP
NM
NM
NM
NM
NM
NM
NP
NP
NP
NP
NP
NP
034682
062381
665833
665836
542767
665855
NM
NM
NM
NM
NM
NM
010552
019508
145834
145837
080729
145856
62
88
83
78
81
77
22q11.1
3p21.1
3p25.3
3p21.1
3p25.3
NP 055154
Q9NRM6
NP 116121
AAM77571
NP 653241
NP 032385
Q9JIP3
NP 598920
NP 602319
NP 665825
NM
NM
NM
NM
NM
008359
019583
134159
134437
145826
68
82
71
90
82
034682
055258
037410
612141
073626
443104
010552
014443
013278
138284
022789
052872
NM 014339
NM 014339
NM 032732
AF458067
NM 144640
A list of known IL-17 family ligands and receptors with their alternate names. The National Center for Biotechnology Information (NCBI) accession
numbers for human protein and mRNA as well as their mouse counterpart. The percent homology is based upon human and mouse protein sequence
similarity.
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Fig. 2. IL-17 receptor family genomic structure: a schematic representation of the sizes of exons (open boxes) and introns. Shaded areas correspond to
the predicted transmembrane domains. Lines connect exons that were joined in sequences from the EST database which represent alternative splicing
events. Exons with (′ ) or (′′ ) have multiple splice donor or acceptor sites evident from sequences in the EST database.
Articular cartilage is a critical component of diarthroidal
joints, providing a low-friction surface for articulation. The
major components of cartilage matrix include aggrecan,
hyaluronic acid, and type II collagen. Aggrecan is a proteoglycan with many negatively charged glycosaminoglycan
(GAG) side chains, which functions to retain water and provide resistance to the compressive forces encountered in the
joint. Type II collagen provides resistance to tensile forces
and helps maintain tissue stability during articulation.
Arthritis is a degenerative disease of articular cartilage
causing gradual permanent compromise of joint function.
Although the incidence of arthritis increases with advanced
age, it can affect people of any age. It already affects more
than 42 million Americans in its chronic form, and by the
year 2020 the United States Center for Disease Control estimates that it will affect more than 60 million, with 12 million
disabled by the disease. Osteoarthritis is a non-inflammatory
disease thought to be caused by the “wear and tear” of
life, perhaps accelerated by physical damage to the joint.
Rheumatoid arthritis is considered an autoimmune disease
marked by increased joint inflammation, T-cell infiltration
of the synovium, and the involvement of many catabolic
cytokines.
Progressive destruction of articular cartilage and bone
along with chronic inflammation of the synovium are
well documented in rheumatoid arthritis. The infiltration
of T-cells into the synovium and the resultant pathology
involves a dynamic interaction between the subintimal endothelial cells and the synovium. Activated T-cells secrete
detectable amounts of interleukin-17A into the synovial
fluid [12]. These increased levels of IL-17A induce a multitude of factors contributing to the degradation of the
articular cartilage and erosion of the underlying bone.
3.1. Ex vivo modeling systems help elucidate IL-17s role
in joint destruction
Interleukin-17A consistently up-regulates IL-6 [13–20]
in both explant cultures and cell cultures of cartilage, synovium, and bone tissues. Interleukin-6, a potent mediator
of inflammation in joints, is known to contribute to the
overall degradation of cartilage in rheumatoid arthritis.
Interleukin-17A has been shown to up-regulate nitric oxide
(NO) production and also to increase the mRNA levels of
inducible nitric oxide synthase (iNOS) in osteoarthritic cartilage, fetal bone, and meniscus explant cultures, as well as
T.A. Moseley et al. / Cytokine & Growth Factor Reviews 14 (2003) 155–174
in cultured osteoblasts and chondrocytes from both normal
and osteoarthritic cartilage [13,21–25]. Increased NO levels
lead to destruction of the extracellular matrix and chondrocyte damage, contributing to the overall reduction in joint
function [26,27].
The enzymatic degradation of cartilage proteoglycans and
collagen is mediated through the release of matrix metalloproteinases (MMPs) and plays an important role in arthritis
[17,28]. IL-17A has been shown to enhance matrix degradation by inducing the release of cartilage proteoglycan GAGs
and collagen fragments, and at the same time inhibit the synthesis of new proteoglycans and collagens [17,18,22,29–31]
The anti-inflammatory cytokine IL-4 has been shown to
overcome the IL-17A-induced inhibition of proteoglycan
synthesis by chondrocytes [26,27].
Interleukin-17A has been shown to synergistically or additively augment many of the destructive effects of IL-1 and
tumor necrosis factor alpha (TNF-␣) in cartilage, synovium,
and meniscus [14,18,19,23]. These cytokines have both been
shown to promote arthritic disease, and inhibition of their
activity by function-blocking antibodies and soluble receptors or antagonists are currently being evaluated clinically
for the treatment of arthritis. While synergy between the
IL-17A and IL-1 pathways has been documented, studies
in IL-1 knockout mice have shown that IL-17A also promotes arthritis in an IL-1 independent manner [32].
The increased levels of IL-17A in the synovial tissues and
fluid of rheumatoid arthritis patients can be a stimulator of
osteoclastogenesis through the up-regulation of osteoclast
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differentiation factor (ODF, osteoprotegerin) [33]. Since osteoclasts function to resorb bone, their increased numbers
and prolonged survival may be contributing factors to the
bone erosion that is common in arthritis (reviewed in [109]).
The direct catabolic actions of IL-17A on cartilage
renders it a potential target in therapeutics for arthritis
[18,22,30,32,34]. Studies using a soluble IL-17 receptor
have shown that blocking IL-17A activity can inactivate
many of its negative effects in animal models of arthritis
and in cell culture experiments.
Table 2 shows a survey of the biological activities of IL-17
cytokines in musculoskeletal tissues with references to the
primary literature. Fig. 3 is a diagrammatical representation
of a chondrocyte highlighting the various matrix components and how they are influenced by the anabolic growth
factors and catabolic cytokines. It illustrates the complex relationships between these many factors.
Interleukin-17A has been the primary IL-17 family member studied in arthritis. IL-17F and IL-17E have a similar effect on cartilage proteoglycan release and inhibition of matrix synthesis [6,24,35]. The source of IL-17A and IL-17F
are the activated T-cells, and it was unclear whether cartilage itself could produce IL-17 cytokines.
3.2. Identification of IL-17B in articular cartilage extract
We hypothesized that there were anabolic factors and
inhibitors in articular cartilage that were yet to be identified
and used a protein chemistry approach to examine an extract
Fig. 3. Cartilage metabolism: a graphical representation of articular cartilage showing the complex relationship between anabolic growth factors and
catabolic cytokines involved in extracellular matrix maintenance.
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Table 2
Review of IL-17 cytokines in musculoskeletal tissues
Model system
Biological effects
Cartilage
Cartilage explants
Articular cartilage explant + IL-17F
↑ Matrix release, IL-6, ↓
proteoglycan synthesis
↑ NO, matrix breakdown, ↓
proteoglycan synthesis
↑ Aggrecanase, NO, ↓ proteoglycan
synthesis
↑ NO
Articular cartilage explant
+ IL-17A, IL-17F
Articular cartilage explant
+ IL-17A, IL-17E
Osteoarthritic articular cartilage
explant + IL-17A
Nasal cartilage explant + IL-17A
↑ Proteoglycan release
↑ Collagen release
Positive interactions
Additive with IL-1␣
Additive with IL-1␣
Synergism with IL-1␣, OSM, TNF-␣
↓ Proteoglycan synthesis, ↑
proteoglycan release
Synergism with TNF-␣
Mouse arthritis
Collagen II-induced arthritis
↑ IL-17A mRNA
IL-17A augments joint destruction
Collagen II-induced arthritis + IL-4
↓ IL-17A, IL-12, IL6, OPGL,
collagen release
↑ RANKL, IL-1, arthritis severity,
chondrocyte death
↓ Cartilage proteoglycan content
↑ IL-17, IL-15 in RA but not OA
patients
Rat arthritis
Adjuvant-induced arthritis
↑ IL-17A, TNF, IFN-␥, ↓ IL-2,
IL-4 in lymph node
↓ Severity of arthritis with
increasing amount of soluble IL-17R
OA cartilage
Chondrocytes
Synovium
Rheumatoid synovium
Blocking IL-17A inhibits arthritis
↑ IL-17A mRNA in PBMC by
IL-15, IL-2, PMA + ionomycin
Primary or 1st passage normal
chondrocytes + IL-17A
↑ NO, IL-1, IL-6, iNOS, COX-2,
stromelysin
Signals through ERK 1/2, JNK, p38,
NF-B
Cell culture + soluble IL-17R
↓ IL-6, MIP-3␣, C-propeptide of
type I collagen
↑ MIP-3␣ mRNA, protein
IL-6, MIP-3␣ additive with soluble
IL-1R, TNFR
Synergism with TNF-␣
Inhibited by IL-4, IL-13
↑ IL-6, Col-I degradation, ↓ Col-I
synthesis
Synergism with TNF-␣
Inhibited by anti-IL-17A
Explant culture + IL-17A
[24]
[25]
[29]
[29]
Independent of IL-1
pathway
No effect on OPG
[32]
Independent of IL-1␣/
pathways
No leukocyte infiltration or
detectable inflammation
No effect on proteoglycan
synthesis rate
[51]
[26]
[30]
[30]
LPS, TNF-␣, IL-8, IL-6 do
not affect IL-17A mRNA in
PBMC
[12]
No change in TGF-
expression
[52]
[53]
Synergism with TNF-␣, additive
with LIF
Cell culture + IL-17A
No change in IL-2, IL-4,
IL-5, IFN-␥ mRNA
No effect of dexamethasone
[18]
↑ NO, iNOS, activation of
MAPKAPK-1,2
↑ Activation MEK-1/2, p44/42,
MKK-3/6, p38, IB-␣
Passaged chondrocytes + IL-17A
Reference
[35,50]
Inhibited by IL-4, IL-13, TGF-1,
IGF-1, TIMP-1, BB-94
↓ Cartilage proteoglycan content, ↑
inflammation
Synovial fluid cytokine levels
Adjuvant-induced arthritis + soluble
IL-17R
Inhibited by dexamethasone,
anti-LIF
Inhibited by anti-LIF, actinonin
Cycloheximide, NF-B inhibitors
Patellae explant culture + IL-17A
Arthritis
No modulation
[6]
Cartilage explants
Collagen II-induced arthritis
+ IL-17A
Single IL-17A injection into mouse
knees
Multiple IL-17A injections into
mouse knees
Negative modulation
PKA, PKC, p38, NF-B,
MEK-1/2 inhibitors
No synergy with IL-1
[21]
Change in SAPK/JNK only
with PKA inhibitors present
[21]
Inhibited by dexamethasone, p38
inhibitor
[13]
[22,31]
No synergism with IL-1,
no effect of IL-10
[34]
[17,18]
T.A. Moseley et al. / Cytokine & Growth Factor Reviews 14 (2003) 155–174
Tissue
Synovial fibroblasts
Fetal bone
Bone explants (RA)
Meniscus
Osteoarthritic menisci
Explants produce IL-17A, IL-6
IL-4 and IL-13 inhibited production
Cell culture + IL-17A
↑ IL-6 mRNA, greater ↑ IL-6 protein
Cell co-culture with resting T-cells
Cell co-culture with resting T-cell
bank
Cell culture + IL-17A
↑ IL-6, IL-8, PGE2
↑ IL-17A expression correlates to
catabolic effect
↑ MMP-1
Cell culture + IL-17A
↑ IL-6, LIF
Synergism with IL-1
Cell culture + IL-17A
↑ IL-8, Gro-␣, Gro-
IL-17R levels increase with
cyclosporin, methotrexate,
dexamethasone
Cell culture + IL-17A
↑ OCIF (= OPG), PGE2
Inhibited by blocking COX-2
Co-culture of osteoblasts and
activated T-cells
Cell culture + IL-17A
Co-culture osteoblasts with bone
marrow cells + IL-17A
Cell culture + IL-17A with
endothelin-1 or PGF2␣
↑ IL-6 by osteoblasts
Effect inhibited by CsA
↑ NO, NOS2 only with TNF-␣
↑ TRAP, PGE2
Inhibited by blocking NF-B
OPG, anti-IL-17A, inhibitors of
COX-2
Synergism with TNF-␣, sequential
effects
Synergism with IL-17A
↑ NO, Ca release
Explant culture + IL-17A and
TNF-␣
↑ Ca release with IL-17A
Bone explants + soluble IL-17R
↓ IL-6, C-propeptide of type I
collagen
Bone explants + IL-17A
↑ IL-6, Col-I degradation, ↓ Col-I
synthesis
Meniscus explant culture + IL-17A
↑ NO, ↑ prostaglandin E2 with
TNF or IL-1
[54]
[55]
Additive with IL-1
No effect on TIMP-1
expression
IL-4 and IL-13 inhibited
production of LIF
Inhibited by blocking p38, PKC,
and tyrosine kinases
Partially inhibited by blocking
NF-B
Partially blocked by soluble IL-17R
[17]
[14]
No effect of pentoxifylline
or indomethacine on IL-17R
[56]
[57]
Not inhibited by anti-IL-17A
neutralizing antibodies
No synergism with IL-6
[16]
Downstream of p44/p42
MAP kinase
[20]
Insensitive to OPG,
NF-B-independent IL-17A
activity?
No effect of IL-17A and
IL-1 on Ca release
[22]
Soluble IL-17R did not
affect IL-6 mRNA in OA
synovium
Synergism with TNF-␣ and IL-1
[15]
[19]
↑ IL-6
Explant culture + IL-17A and
TNF-␣
IL-10 had no effect on
IL-17A production
[58]
[33]
[59]
[22]
T.A. Moseley et al. / Cytokine & Growth Factor Reviews 14 (2003) 155–174
Bone
Osteoblast
Explant culture
[18]
[23]
This represents a survey of the biological activities of the IL-17 cytokine family in related musculoskeletal tissues.
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of 2 kg of bovine articular cartilage. Cartilage proteins
were extracted in guanidine, fractionated on cation exchange and reverse-phase HPLC columns, then run on 2D
SDS-PAGE. One protein identified using this technique was
the then-unknown IL-17B, and based on the intensity of the
Coomassie-stain we estimate that it is present at a concentration of about 50 ng/g of bovine articular cartilage. The
presence of IL-17B mRNA in chondrocytes was confirmed
using northern blot and RT-PCR. Fig. 4 shows the expression of IL-17B by immunohistochemistry of chondrocytes
in three zones of normal bovine articular cartilage. While
the surface chondrocytes show little reactivity, the mid and
deep zones are IL-17B positive. The polyclonal antibody
to IL-17B shows no cross-reactivity to IL-17A, although it
has not been tested against the remaining IL-17 cytokines.
The presence of IL-17B in cartilage and its synthesis by
chondrocytes led us to search for the presence of additional
IL-17 receptors in cartilage. Immunoblot of cartilage extracts show the presence of both the long and short forms
of IL-17RH1. The long form of IL-17RH1 is a transmembrane receptor which has been shown to bind to IL-17B and
IL-17E and cause activation of NF-B [36]. Alternatively
spliced variants of this protein are secreted as soluble proteins since they lack the transmembrane domain.
We have identified and cloned a third receptor sharing
∼22% identity and 34% similarity with IL-17R and named it
Fig. 4. Chondrocytes in bovine articular cartilage highly express IL-17B: immunohistochemistry of articular chondrocyte cell surface shows IL-17B
expression in mid and deep zones but less in surface zone. This figure is a compilation of three separate images taken on a Zeiss LSM 510 confocal
microscope. Staining of IL-17B was done using IL-17B specific rabbit antibody (anti-N-terminal-IL-17B) followed by FITC labeled anti-rabbit IgG
secondary antibody. Nuclear staining was done by propidium iodide.
T.A. Moseley et al. / Cytokine & Growth Factor Reviews 14 (2003) 155–174
Fig. 5. Interleukin-17 receptor-like molecule (IL-17RL) is expressed in
human articular chondrocytes: immunohistochemistry of chondrocytes
in mid- and deep-zone articular cartilage show surface expression of
IL-17RL. Image was taken on a Zeiss LSM 510 confocal microscope.
Staining of IL-17RL was done using IL-17RL specific rabbit antibody
(anti-N-terminal-IL-17RL) followed by FITC labeled anti-rabbit IgG secondary antibody. Nuclear staining was done by propidium iodide.
IL-17 receptor-like (IL-17RL) [9]. The cytoplasmic domains
of these proteins are even more conserved, sharing 25%
identity and 41% similarity across their membrane domains.
Fig. 5 shows that IL-17RL is produced by chondrocytes in
the mid- and deep-zone human articular cartilage. As with
IL-17RH1, alternatively spliced variants of this protein are
also secreted since they lack the transmembrane domain. The
antibody used for histochemistry in Fig. 5 recognizes the
extracellular domain and thus cannot distinguish between
soluble and transmembrane isoforms.
During development, cartilage is formed by the actions
of anabolic growth factors including bone morphogenetic
proteins (BMPs), cartilage derived morphogenetic proteins
(CDMPs), and growth and differentiation factors (GDFs).
In diseases such as arthritis, cartilage is destroyed through
the actions of catabolic cytokines including IL-17, IL-1,
and TNF-␣. During the homeostasis of healthy tissues, it is
likely that there is a balance between anabolic and catabolic
factors. The exact composition of factors contributing to this
balance may affect a tissue’s potential for repair and regeneration. Although bone and articular cartilage are adjacent
tissues there is a profound difference in their potential for
regeneration and repair; articular cartilage is recalcitrant to
repair while bone has immense potential for regeneration.
The differences in innate regeneration potential may be
due to concentration of morphogens and associated binding
proteins such as noggin chordin and DAN family [37]. For
example, in partial thickness defects confined to articular
163
cartilage there is no attempt to initiate repair. However, in
full thickness defects, when the subchondral bone is penetrated, there is initiation of repair of articular cartilage
implying a role for subchondral bone. The bone matrix is a
repository of bone morphogenetic involved in cartilage and
bone morphogenesis. Thus, the difference between bone and
articular cartilage may be due endogenous growth factors
and morphogenetic proteins and associated binding proteins
and catabolic cytokines. Other factors that may influence
the lack of repair of damaged cartilage are that cartilage
is a tissue comprised of immobile cells fixed in a tightly
cross-linked extracellular matrix. Also, unlike in bone, in
cartilage there is no population of mesenchymal progenitor
cells. The initiation of cartilage morphogenesis is governed
by BMPs. The newly formed articular cartilage is maintained
by insulin-like growth factor-1 (IGF-1) and platelet-derived
growth factors (PDGFs). The homeostasis of articular cartilage is the function and balance of anabolic morphogenetic
proteins, and catabolic cytokines such as interleukin-1
(IL-1), interleukin-17 (IL-17), tumor necrosis factor alpha
(TNF-␣). Therefore at steady state the articular cartilage is
maintained by an interplay between cartilage morphogens,
cognate antagonists and catabolic cytokines (Fig. 3).
4. IL-17 in cancers
The mis-regulation of growth factor pathways is a common feature of many cancers. Although there are no published reports describing genetic linkage of either IL-17
cytokines or receptors directly to cancers, there is evidence
that IL-17s are active in cancers. IL-17A has been shown to
promote angiogenesis in tumor models and correlates well
with the numbers of blood vessels in human ovarian cancers
[38]. IL-17A promotes tumorgenicity of human cervical tumors in nude mice and is associated with an increased level
of IL-6 expression at the tumor sites [39]. Increased levels
of IL-6 correlate well with the invasiveness of cervical tumors [40]. These reports indicate a role of IL-17 cytokines
in promoting tumor. However, other lines of evidence
indicate that IL-17A may protect against tumors by promoting immune system-mediated tumor rejection [41–43].
Table 3 is a survey of the biological activities of IL-17s in
cancers.
4.1. IL-17 in prostate cancer
Prostate cancers generally metastasize to bones such as
the spine and the pelvis. Prostate metastases lead to both
osteoblastic and osteolytic lesions in bone. The dynamic
regulatory networks at the interface of prostate carcinoma
metastases and bone are indicated in a simplified form in
Fig. 6. The interactions between stromal cells and epithelial cells are critical for tumor progression and metastasis
in prostate. The carcinoma cells secrete morphogens and
growth factors such as BMPs, IGF and TGF- which act on
164
T.A. Moseley et al. / Cytokine & Growth Factor Reviews 14 (2003) 155–174
Table 3
Review of IL-17 cytokines in cancer
Tissue
Model system
Biological effects
Prostate carcinoma
Biopsy
Fibrosarcoma
IL-17A overexpression,
rejection model
Altered IL-17RL distribution
in grades of cancer
↑ Rejection of IL-17A
expressing tumor cells
CHO cells
IL-17A overexpression,
nude mice
Cell culture + IL-17B
↑ Matrigel invasion, lung
mets, NK activity
THP-1 cell culture
+ IL-17B
THP-1 cell culture
+ IL-17C
↑ TNF-␣, IL-1
Leukemic monocyte
Viral integration site
analysis
↑ Evi27 in murine myeloid
leukemias
Cervical tumors
Cervical tumor cells
+ IL-17A
IL-17A overexpression,
nude mice
↑ IL-6, IL-8 mRNA, protein
Ovarian cancer
IL-17A overexpression,
mice
Ovarian cancer biopsy
Negative
modulation
No modulation
Reference
[9]
T-cell
dependent
↑ TNF-␣, IL-1
Murine leukemia
Hematopoietic
Positive
interactions
Anti-CD4,
CD8, CD90
Anti-asialo GM1
[41]
No effect on proliferation,
sq tumor growth
No effect on IL-6, IL-8,
TNF-␣, IFN-␥, IL-3,
G-CSF
[42]
No effect on IL-6, IL-1␣,
IFN-␥, G-CSF
No effect on IL-6, IL-1␣,
IFN-␥, G-CSF
[60]
[60]
[8]
No effect on in vitro
proliferation
↑ Tumor size, macrophage
recruitment, IL-6
↓ Tumor size in
immunocompetent mice
+ Correlation between
IL-17A and angiogenesis
[7]
[39,40]
[39]
No effect on tumor size in
nude mice
No correlation to tumor
stage, survival
[43]
[38]
This represents a survey of the biological activities of the IL-17 cytokine family in cancer.
Fig. 6. Cancer metastasis to bone: a graphical representation of the authors views of how the progression of a metastatic tissue such as prostate cancer
can lead to the progression of osteosclerosis as well as osteolysis.
T.A. Moseley et al. / Cytokine & Growth Factor Reviews 14 (2003) 155–174
165
Fig. 7. Interleukin-17 receptor-like molecule (IL-17RL) is expressed in human prostate: immunohistochemistry of normal prostate and increasing Gleason
grades of prostate cancer show surface expression of IL-17RL. The cancerous tissues show some evidence of a shift from epithelial expression to stromal
expression as the cancer becomes more severe. Image was taken on a Zeiss LSM 510 confocal microscope. Staining of IL-17RL was done using IL-17RL
specific rabbit antibody (anti-N-terminal-IL-17RL) followed by FITC labeled anti-rabbit IgG secondary antibody. Nuclear staining was done by propidium
iodide (image used with permission of the author, D.R. Haudenschild and publisher).
cells in the bone. In response to PTH and PTHrp osteoblasts
and stromal cells secrete RANK ligand (RANKL) which
binds to receptor activator of NF-B (RANK) on osteoclast precursors to differentiate into functional multinu-
cleate osteoclasts. The bioavailability of RANKL to its
receptor RANK is determined by the activity and affinity of a soluble decoy receptor osteoprotegerin (OPG)
to RANKL. Interleukin-1, interleukin-17, tumor necrosis
Fig. 8. Cellular signaling of IL-17 cytokines: a graphical representation of the known IL-17 cytokines and ligands. The transmembrane receptors as
well as their soluble decoy receptor versions are shown. Some of the signal transduction pathways are represented with question mark in the place of
unknown pathways. There are no known receptors for IL-17C, IL-17D and IL-17F. There are no known ligands for IL-17RL, IL-17RD or IL-17RE.
166
Table 4
Review of IL-17 cytokine signal transduction
Cytokine used
Signal transduction through
these actions
Inhibitors of signal transduction
Subepithelial
myofibroblasts
Embryonic fibroblasts
SEMF cell culture + IL-17A
NF-B, p42/44 ERK 1/2, p38
Inhibitors of MAPK
Cell culture + IL-17A,
TRAF-6 KO
Cell culture + IL-17A
TRAF-6, IKK, JNK, NF-B,
AP-1
JAK 1,2,3, Tyk 2, STAT 1,2,3,4
↑ Stability of G-CSF mRNA by
↓ degradation
Identification of IL-17A receptor
Monocytic leukemia
NIH-3T3 cells
Peripheral blood
leukocyte
Pancreatic
myofibroblasts
Glioblastoma
Cell culture + IL-17A
MEK-1/2 and p38
Cell culture + IL-17A
Intestinal epithelium
Cell culture + IL-17A
Macrophage
Cell culture + IL-17A
↑ IB-␣ mRNA, protein
degradation
↑ NF-B activation, p65/p50
subunits, TRAF-6
NF-B, AP-1, CREB, and ↑
calcium flux
Vascular epithelium
Cell culture + IL-17D
Cell culture + IL-17F (ML-1)
NF-B activation
ERK 1/2
OA cartilage
OA cartilage
Explant culture + IL-17A
Passaged chondrocytes
+ IL-17A
NF-B activation
MEK-1/2, p44/42, MKK-3/6,
p38, IB-␣, MAPKAPK-1,2
Inhibitors of PKA, PKC, p38,
NF-B, MEK-1/2
Chondrocytes
Cell culture + IL-17A
ERK 1/2, JNK, p38, NF-B
Inhibitors of p38, IKK
Not involved in signaling
Other effects
Reference
↑ IL-6 mRNA stability
[85]
TRAF-2
TRAF-6 directly binds
IL-17R
[103]
JAK/STAT
↑ G-CSF mRNA stability
Affinity lower than
biological activity
↑ IL-6 mRNA stability
Inhibitors of MEK-1/2 and p38
[44]
[104]
[105]
[106]
[75]
TRAF-2 not required
Inhibitors of PKC, MAPK
[107]
No activation of p38 or JNK
This represents a survey of the signal transduction pathways of the IL-17 cytokine family in a variety of tissues examined.
[80]
Activation of SAPK/JNK
only with PKA inhibitors
present
[65]
[72]
[25]
[21]
[13,108]
T.A. Moseley et al. / Cytokine & Growth Factor Reviews 14 (2003) 155–174
Experimental system
Table 5
Review of biological activities of IL-17 cytokines in the immune system
Tissue
Immunology
Dendritic cell
progenitor
Neutrophil migration
T-cell proliferation
Macrophage
Biological effects
Bone marrow cells + IL-17A
and GM-CSF
IP injection of IL-17B,
neutrophil count
Mutant Herpesvirus saimiri
(no IL-17) infecting T-cells
Cell culture + IL-17A or
vIL-17
Cell culture + IL-17A
↑ CD11c, CD40, CD80,
CD86, MCH class II
↑ Neutrophil influx
Cell culture + IL-17A
Hematopoiesis
Bone marrow cells
Transplantation
Vascular
Kidney
Heart
Vasculature
Vascular endothelium
Vascular endothelium
Negative modulation
No modulation
[7]
↑ Proliferation
Thoracic aorta transplants
+ soluble IL-17R:Fc
Renal transplants, rejection
↓ MNC infiltration early
[62]
[63]
↑ MMP-9, PGE2, COX-2,
STAT 1,3 phosphorylation,
AP-1 binding
↑ TNF-␣
↓ Myeloid progenitor cell
proliferation
Reference
[61]
No effect on viral replication or
transformation of cells
Colony formation in
methylcellulose + IL-17D
Colony formation of marrow
cells + IL-17F
Cell culture + IL-17A
Heart transplant + soluble
IL-17R:Fc
Positive interactions
COX inhibitor, IL-4, IL-10,
IL-13, inhibitors of p38,
MEK-1/2, NF-B
Blocked by PGE2 through
Egr-1
No effect on MMP-1, MMP-3,
JNK/SAPK phosphorylation
[28]
[64]
[65]
No effect of IL-17F on colony
formation
↑ IL-6 protein
[4]
[66]
No effect of IL-17R:Fc on
chronic rejection
↑ IL-17A in renal transplant
rejections
↑ Cardiac allograft median
survival time
↓ T-cell proliferation, ↑
allograft survival
[67]
[68–70]
[71]
[61]
Cell culture + IL-17D
↑ IL-6, IL-8, GM-CSF
Capillary tubule formation
+ IL-17F
HVEC + IL-17F
↓ Tubule formation
[4]
↑ TGF-1, TGF-2, MCP-1,
Lymphotoxin-, IL-2
↑ IL-6, IL-8
[4]
HUVEC + IL-17F (ML-1)
Signals through
NF-B activation
Signals through ERK
1/2
IL-1, IL-2, IL-4, IL-5, IL-10,
IL-12, IFN-␥, TNF-␣
No activation of p38 or JNK
T.A. Moseley et al. / Cytokine & Growth Factor Reviews 14 (2003) 155–174
Viral IL-17
Model system
[65]
[72]
167
168
Table 6
Review of biological activities of IL-17 cytokines in other tissues
Tissue
Model system
Biological effects
Positive interactions
Negative modulation
No modulation
Reference
Ischemia animal model
↑ IL-17A mRNA locally after
ischemia
↑ IL-17A mRNA systemically
Neurons
In situ hybridization/antibody
stains
IL-17B expressed by motor
and sensory neurons
[74]
Glioblastoma
Rat cell culture + IL-17A
↑ IB-␣ mRNA, IB-␣
protein degradation
↑ IL-6, IL-8 mRNA
[75]
Synergism with IL-1
↑ IL-6 mRNA
Synergism with IFN-␥
↑ IL-8 mRNA
Synergism with TNF-␣, IFN-␥
↑ ICAM-1, MHC class I,
CD40, RANTES, IL-1␣
↑ ICAM-1, RANTES
↑ ICAM-1 synergy with IL-17A
↑ CCL-20 mRNA (= MIP-3␣)
Synergism with TNF-␣
Brain
[73]
[73]
Skin
Keratinocyte cell culture
+ IL-17A
Keratinocyte cell culture
+ IL-17A
Keratinocyte cell culture
+ IFN-␥
Keratinocyte cell culture
+ TNF-␣
Keratinocyte cell culture
+ IL-17A
Foreskin fibroblast + IL-17F
Foreskin fibroblasts + IL-17B
Foreskin fibroblasts + IL-17C
Foreskin fibroblasts + IL-17A
Digestive tract
Intestinal epithelium
Intestinal epithelia cells
+ IL-17A
↑ Of RANTES blocked by
IL-17A
↑ Of RANTES blocked by
IL-17A
IL-1␣, IL-15, GAPDH,
proliferation
ICAM-1, HLA-DR, MHC class
I, CD40
MHC class I, CD40
[76,77]
ICAM-1
[77]
[76,77]
[78]
↑ IL-8, G-CSF protein
No effect on IL-6
No effect on IL-6
↑ IL-6, IL-8, ICAM-1
↑ NF-B activation, p65/p50
subunits
↑ CINC
[76]
[6]
[60]
[60]
[79]
[80]
Synergism with IL-1,
TRAF-6 dependent
TRAF-2 not required
[80]
↑ IL-8 mRNA, protein
↑ MCP-1
[80]
[80,81]
[82]
[82]
Intestinal epithelium
Helicobacter pylori infection
↑ IL-17A when infected
↑ IL-8 mRNA, protein
Intestinal epithelium
Fetal cell cultue + IL-17A
↑ IL-8 mRNA, protein
Synergism with IFN-␥
↑ MCP-1 mRNA, protein
Synergism with IFN-␥
[81]
Pancreas
Pancreatic myofibroblast cells
+ IL-17A
↑ IL-6 mRNA, protein
Synergism with TNF-␣, IFN-␥
[83]
↑ Stability of TNF-␣-induced
IL-6 mRNA
IFN-␥ alone does not affect
IL-8
IFN-␥-induced IL-6 mRNA not
stabilized
[81]
[83]
T.A. Moseley et al. / Cytokine & Growth Factor Reviews 14 (2003) 155–174
[75]
Colon carcinoma
T84 cell culture with IL-17A
↑ Tight junction formation
↑ Claudin-1,2 mRNA, protein
Rat jejunitis
Indomethacin injection, small
intestine examined
↑ IL-17BR
Subepithelial
myofibroblasts
SEMF cell culture + IL-17A
↑ IL-6, IL-8, MCP-1 protein
IL-17A
[84]
[84]
[7]
Synergism with TNF-␣ and
IL-1, signals through NF-B,
p38, p42/44 ERK
[85]
Inhibited by p38 inhibitor
[85]
Lung
Asthma
Primary bronchial epithelial
cells + IL-17A
Primary bronchial epithelial
cells + IL-17A
Primary bronchial epithelial
cells + IL-17F (ML-1)
Intratracheal instillation of
IL-17A
Bronchoalveolar lavage
specimens
Bronchial fibroblast culture
+ IL-17A
Serum IL-17A levels in asthma
patients
Klebsiella pneumoniae
challenged lung
K. pneumoniae challenge,
IL-17R KO
IL-17A overexpression in lung,
adenoviral
Rat neutrophil culture
+ IL-17A
Bronchial epithelial cells
+ IL-17A
Severe lung inflammation in
humans
Severe lung inflammation in
mice
↑ IL-17A in lungs of asthma
patients
↑ IL-8, Gro-␣, G-CSF mRNA,
protein
↑ IL-6
↑ IL-6, IL-8 protein
No effect on RANTES, ICAM
expression
↑ IL-6, IL-8 ICAM-1 mRNA,
protein
[86]
Synergism with TNF-␣
Synergism with IFN-␥
[87]
Dexamethasone inhibits
neutrophil recruitment
↑ IL-17A in eosinophils of
asthma patients
↑ IL-6, Gro-␣ mRNA in
normal and asthma
↑ IL-11 mRNA only in
asthmatic patients
No significant elevation of
IL-17A
↑ IL-17A in lungs after
bacterial challenge
↑ Mortality in challenged
IL-17R KO mice
↑ TNF-␣, IL-1, MIP-2,
G-CSF
No effect on eotaxin, RANTES
mRNA, c-JUN or JNK
activation
No recruitment of eosinophils,
macrophages, lymphocytes
[72,88]
[89,90]
[91]
[91]
Dexamethasone inhibits
IL-17A-induced IL-6, IL-11
No effect of IL-17A on IL-11
in non-asthma
[91]
[92]
Alcohol inhibits ↑ IL-17A
after bacterial challenge
↓ MIP-1␣-1,-2, G-CSF, SCF
in challenged KO mice
[93,94]
[95]
[93]
Synergism with TNF-␣
↑ Of IL-8 blocked by
hydrocortisone
No effect on myeloperixidase
activity
No effect of IL-17A on
neutrophil migration
↑ IL-17A, IL-6, IL-8, TNF-␣
↑ IL-17A, IL-1, TNF-␣,
IL-6, MIP, MCP, etc.
[86]
[86]
[87]
PD98059 (MEK-1/2 inhibitor)
IL-17A augments IFN-␥’s
effect on ICAM
↑ Neutrophil recruitment
↑ IL-8 mRNA, protein
Dexamethasone on IL-8
production
T.A. Moseley et al. / Cytokine & Growth Factor Reviews 14 (2003) 155–174
↑ Stability of TNF-␣-induced
IL-6 mRNA
Inhibited by MAPK inhibitors
[96]
[90]
[97]
No effect on IL-4, IL-5, IL-18
mRNA
[98]
169
170
Tissue
Kidney
Nephrotic disease
Renal epithelia
Renal biopsy
Renal carcinoma
Miscellaneous
Mouse IL-17E
transgenic mouse
NIH-3T3 cells
Model system
Biological effects
Urine samples of MCNS,
IgAN, healthy patients
Primary tubular epithelial cells
+ IL-17A
Segmental glomerulosclerosis
↑ IL-17A excretion in
nephrotic patient
↑ IL-6, IL-8, MCP-1,
RANTES∗
293, TK-10 cell culture
+ IL-17E
↑ NF-B-responsive luciferase
activity, IL-8 protein
[36]
Myosin L-chain 2 promotor
Smaller, jaundiced, ↑ cytokine
expression
Neutrophilia, eosinophilia,
multiorgan inflammation
↑ IL-6 protein
[102]
Cell culture + IL-17A
Positive interactions
Synergism with CD40L
Negative modulation
Inhibited by blocking NF-B
No modulation
Reference
No age or gender-related
differences
No effect of IL-17A alone on
RANTES
No IL-17A mRNA detected in
any biopsy
[99]
[69,70,100]
[101]
[102]
Signals through NF-B
activation
[63]
T.A. Moseley et al. / Cytokine & Growth Factor Reviews 14 (2003) 155–174
Table 6 (Continued )
T.A. Moseley et al. / Cytokine & Growth Factor Reviews 14 (2003) 155–174
factor (TNF) and their cognate signaling systems have a role
in osteoclastogenesis. The degradation of bone matrix by
multinucleate osteoclasts releases growth factors and morphogens from the extracellular matrix. The regulatory networks in the breast/prostate cancer metastasis to bone are
reciprocal and dynamic as illustrated by the secretion of
BMPs, IGF and TGF- family of ligands, cognate receptors
and antagonists and binding proteins for the growth factors
and morphogens. The binding proteins include IGF-binding
proteins, latent TGF- binding proteins and BMP antagonists Noggin, Chordin, Gremlin, Cereberus and DAN. The
interleukin-17 family of cytokines may thus play a role in
bone resorption and lead up to osteolytic fractures.
IL-17A is expressed only in T-cells. We therefore
searched for the expression of other IL-17 cytokines in
normal and cancerous prostate to gain insight into their
possible roles in this tissue. Current versions of the EST
database indicate that IL-17B, IL-17C and IL-17E cytokines are expressed in the prostate. We have shown that
IL-17RL is expressed in human prostate by immunohistochemistry and RT-PCR [9]. It is noteworthy that in prostate
carcinoma the immunoreactivity to extracellular domain
shifted to the stroma with advancing Gleason grades, and
that there is a progressive loss of staining in the epithelium
(Fig. 7). We have quantitative RT-PCR (TaqMan) evidence
that exon usage is tissue specific which implies that there
are regulatory factors that control the RNA splicing of
IL-17RL.
The presence of soluble IL-17RH1 and IL-17RL decoy
receptors, and the tissue-specific regulation of IL-17RL
mRNA splicing to generate different receptor isoforms, hint
that the regulation of IL-17 pathways is complex and tightly
regulated.
5. IL-17 signaling pathways
The emerging knowledge about the IL-17 family and
IL-17 receptors has set the stage for investigation of signaling pathways. IL-17 Receptor (IL-17R) activates extracellular signal-regulated protein kinase (ERK), c-jun N-terminal
kinase (JNK) and p38 MAP kinase pathways [13,21,44,45].
These signaling pathways result in up-regulation of IL-6,
IL-1 and NF-B [46]. The current status of the signaling
pathways is presented diagrammatically in Fig. 8, and in
Table 4. The emerging novel receptors include IL-17RL
(also designated IL-17RC), IL-17RD and IL-17RE. The fact
that IL-17 family of ligands unexpectedly revealed a cystine
knot similar to the BMP/TGF-, PDGF and NGF indicate
the potential for cross-talk with other morphogen signaling pathways. The potential for IL-17RL and IL-17RH1
to exist as both soluble decoy receptors and signaling
transmembrane receptors presents an additional level of
control. The soluble decoy receptors may bind to the IL-17
family of ligands selectively and reduce or eliminate their
bioavailability.
171
6. IL-17 biological activity in other tissues
Interleukin-17 cytokines have been studied in a variety of
other tissues and diseases. A large body of evidence shows
that IL-17A and IL-17F (ML-1) are involved in asthma.
Asthma is marked by the recruitment of neutrophilic leukocytes into the airway, a process thought to be regulated by
T-cells through pro-inflammatory cytokines such as IL-6 and
TNF-␣. IL-17A and IL-17F expression are increased in asthmatic versus normal patients, and both cytokines have been
shown to induce IL-6 and IL-8 expression [7,29,34,35,103].
This topic is nicely reviewed in [47–49]. Tables 5 and 6
present a survey of the biological activities in the immune
system and various other tissues not discussed individually
within this text.
Acknowledgements
We thank Rita Rowlands for help in the preparation of the
manuscript including outstanding bibliographic assistance.
Our research is supported by grants from the US Army
Medical Research Acquisition Activity (AMRAA), Department of Defense, Award No. DAMD17-02-1-0021; and from
the National Institute of Health (NIH), Award No. 1 R01
AR47345-01A2.
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