The expanded family of class II cytokines that share the IL-10
receptor-2 (IL-10R2) chain
Raymond P. Donnelly,*,1Faruk Sheikh,* Sergei V. Kotenko,†and Harold Dickensheets*
*Division of Therapeutic Proteins, Center for Drug Evaluation & Research, Food and Drug Administration,
Bethesda, Maryland; and†Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry
of New Jersey, Newark
lated cytokines have recently been discovered.
These include IL-22, IL-26, and the interferon-?
(IFN-?) proteins IFN-?1 (IL-29), IFN-?2 (IL-
28A), and IFN-?3 (IL-28B). The ligand-binding
chains for IL-22, IL-26, and IFN-? are distinct
from that used by IL-10; however, all of these
cytokines use a common second chain, IL-10 re-
ceptor-2 (IL-10R2; CRF2-4), to assemble their
active receptor complexes. Thus, IL-10R2 is a
shared component in at least four distinct class II
cytokine-receptor complexes. IL-10 binds to IL-
10R1; IL-22 binds to IL-22R1; IL-26 binds to
IL-20R1; and IFN-? binds to IFN-?R1 (also known
as IL-28R). The binding of these ligands to their
respective R1 chains induces a conformational
change that enables IL-10R2 to interact with the
newly formed ligand-receptor complexes. This in
turn activates a signal-transduction cascade that
results in rapid activation of several transcription
factors, particularly signal transducer and activa-
tor of transcription (STAT)3 and to a lesser de-
gree, STAT1. Activation by IL-10, IL-22, IL-26,
or IFN-? can be blocked with neutralizing antibod-
ies to the IL-10R2 chain. Although IL-10R2 is
broadly expressed on a wide variety of tissues, only
a subset of these tissues expresses the ligand-bind-
ing R1 chains. The receptors for these cytokines
are often present on cell lines derived from various
tumors, including liver, colorectal, and pancreatic
carcinomas. Consequently, the receptors for these
cytokines may provide novel targets for inhibiting
the growth of certain types of cancer. J. Leukoc.
Biol. 76: 314–321; 2004.
Several novel interleukin (IL)-10-re-
Key Words: IFN-? ? STAT3/STAT1 ? hepatocytes ? 1SGF3 ? IL-
Several comprehensive reviews have been published in recent
years regarding the interleukin (IL)-10 signal-transduction
pathway and the biological activities that are induced by
signaling through IL-10 receptors (IL-10Rs) [1, 2]. In this
overview, we will briefly summarize the sequence of events by
which binding of IL-10 to the IL-10R complex leads to the
induction of gene expression in macrophages. However, the
primary focus of this overview will be to discuss the role of the
IL-10R2 chain as a shared component in the receptor com-
plexes for several novel IL-10-related cytokines. These include
IL-22, IL-26, and the interferon-? (IFN-?) proteins IFN-?1
(IL-29), IFN-?2 (IL-28A), and IFN-?3 (IL-28B).
The IL-10R2 chain was originally shown by Kotenko et al.
 to be an essential component of the IL-10R complex. IL-10
initially binds to its specific ligand-binding chain IL-10R1 .
Once IL-10 is bound to IL-10R1, IL-10R2 is required to
assemble the active IL-10R complex. Ligand-mediated assem-
bly of the IL-10R1 and IL-10R2 chains catalyzes rapid acti-
vation of signal transducer and activator of transcription
(STAT)3 and induction of STAT3-responsive genes. For sev-
eral years, it was assumed that IL-10R2, like IL-10R1, is a
unique component of the IL-10R complex. However, it is now
clear that the IL-10R2 chain is used for signaling by several
other class II cytokines, including IL-22, IL-26, and the IFN-?
proteins. Therefore, the IL-10R2 chain is a common compo-
nent of the functional receptor complexes for multiple class II
THE IL-10R COMPLEX
IL-10 was originally identified as a soluble factor produced by
activated murine CD4?T helper-type 2 (Th2) cells, which can
inhibit production of cytokines such as IL-2 and IFN-? by Th1
cells . Shortly thereafter, it was determined that the ability
of IL-10 to inhibit cytokine production by T cells was indirectly
mediated via its inhibitory effects on antigen-presenting cells
(APC) such as monocytes, macrophages, and dendritic cells
(DC) [6, 7]. Therefore, IL-10 acts directly on APC to inhibit
expression of costimulatory surface molecules such as major
histocompatibility complex (MHC) class II and B7 as well as
cytokines that are necessary for optimal T cell activation [8, 9].
By inhibiting expression of these molecules by APC, IL-10
indirectly suppresses activation of T cells and production of T
cell-derived cytokines such as IFN-? and IL-2. In addition to
1Correspondence: FDA-CDER, Division of Therapeutic Proteins, HFM-538,
1401 Rockville Pike, Rockville, MD 20852. E-mail: email@example.com
Received February 27, 2004; revised April 8, 2004; accepted April 9, 2004;
314 Journal of Leukocyte Biology
Volume 76, August 2004
its effects on APC, IL-10 can exert direct effects on B and T
lymphocytes (CD4?and CD8?), natural killer (NK) cells, mast
cells, and eosinophils. For example, IL-10 is a potent growth
factor for activated B cells  and can prevent activation-
induced apoptosis in T cells . Although IL-10 primarily
inhibits T cell activation via its inhibitory effects on APC, T
cells express IL-10Rs, and IL-10 can act directly on T cells to
inhibit production of certain cytokines, particularly IL-2
The ligand-binding chain of the IL-10R complex, IL-10R1,
was first reported in 1993 . The cDNA for the mouse
IL-10R1 gene was isolated from cDNA libraries prepared from
a murine mast cell line, MC/9, and a murine macrophage cell
line, J774. Expression of these cDNAs in COS-7 cells gener-
ated an IL-10R protein (?110 kDa), which bound radiolabeled
IL-10 with an affinity comparable to that previously shown for
native IL-10Rs. Furthermore, when expressed in a mouse
pre-B cell line, Ba/F3, the recombinant murine (rm)IL-10R1
chain enabled these cells to proliferate in response to IL-10
The gene for the human (h)IL-10R1 chain was cloned from
a cDNA library prepared from a human Burkitt lymphoma cell
line, BJAB . The hIL-10R1 gene encodes a 3.6-kb mRNA
transcript and similar to the mIL-10R1 gene, generates an
IL-10-binding protein, 90–110 kDa in size when expressed in
COS-7 cells. The full-length protein consists of 557 amino
acids and is ?60% identical to the murine homologue. Se-
quence analysis of the mIL-10R1 and hIL-10R1 proteins re-
vealed that the actual molecular mass of these molecules (?60
kDa) was much less than that determined by chemical cross-
linking and sodium dodecyl sulfate-polyacrylamide gel elec-
trophoresis. These findings indicated that a large portion of the
total mass of the IL-10R1 molecule is a result of carbohydrate.
The hIL-10R1 chain exhibits a dissociation constant for IL-10
in the range of 200–250 pM when expressed in Ba/F3 cells.
For IL-10 to transduce a signal from the cell membrane to
the nucleus, it requires the participation of another class II
cytokine receptor, IL-10R2, originally known as CRF2-4,
which was initially cloned as an orphan receptor encoded by a
gene, CRFB4, closely linked to the IFN-? receptor (IFN-?R)
genes on chromosome 21 . The precise function of this
receptor chain was unknown until 1997 when Kotenko et al. 
showed that CRF2-4 was in fact an essential second chain in
the IL-10R complex. IL-10 mediates signal transduction in
IL-10R-positive target cells by activating the receptor-associ-
ated Janus tyrosine kinases (JAK)1 and Tyk2 . JAK1 is
associated with IL-10R1, and Tyk2 is associated with IL-10R2
(CRF2-4). The ligand-mediated association of the IL-10R1 and
IL-10R2 chains activates these kinases and catalyzes phos-
phorylation of specific tyrosine residues on the intracellular
domain of the IL-10R1 chain . Either or both of these
phosphotyrosine residues can serve as docking sites for the
latent cytosolic transcription factor STAT3, which binds to the
activated (tyrosine-phosphorylated) receptor via its central Src
homology 2 domain and is in turn phosphorylated on tyrosine
by the activated receptor-associated Janus kinases. This re-
sults in the formation of phosphorylated STAT3 homodimers,
which then translocate to the nucleus and bind with high
affinity to STAT-binding elements in the promoters of various
Several groups have used cDNA microarray screens to examine
the repertoire of genes that are induced by IL-10 in macrophages
[18, 19]. These studies have facilitated the identification of a
number of IL-10-inducible genes. These include a variety of
membrane receptors, secretory proteins, and transcription factors.
Activation of gene expression by IL-10 is STAT3-dependent [19,
20]. IL-10 also inhibits induction of many genes by lipopolysac-
charide (LPS), including proinflammatory cytokines such as tumor
necrosis factor ? and IL-1?. Although the exact mechanism by
which IL-10 inhibits expression of proinflammatory genes has not
yet been defined, the inhibitory effects of IL-10 also appear to be
STAT3-dependent [20, 21].
THE IL-22R COMPLEX
IL-22 was originally discovered as an IL-10-related T cell-
derived inducible factor . IL-22 exhibits ?22% homology
to IL-10 at the amino acid level . IL-22 is coexpressed
together with IFN-? and IL-26 by activated T cells . IL-22
is preferentially expressed by Th1 cells. Therefore, IL-22 can
be classified as a Th1-type lymphokine together with IFN-?
and IL-26. In fact, the genes for IL-22, IFN-?, and IL-26 are
located in close proximity to one another on chromosome
12q14?3. This suggests that the proteins encoded by these
genes may share certain functional activities. This topic will be
discussed in greater detail later in this overview.
IL-22 signals through a receptor complex composed of the
ligand-binding chain IL-22R1 (CRF2-9) and the accessory
chain IL-10R2 (CRF2-4) [24, 25]. IL-22 strongly activates
STAT3 and to a lesser degree, STAT1 and STAT5 . It was
previously believed that the IL-10R2 chain is a unique com-
ponent of the IL-10R complex. Demonstration that IL-10R2 is
also an essential part of the IL-22R complex provided the first
example of the shared use of IL-10R2 by a distinct class II
cytokine receptor complex. As shown in Figure 1A, a neu-
tralizing anti-IL-10R2 monoclonal antibody (mAb), 1A8.3 ,
blocked activation of STAT3 by IL-22 but not IL-20 in an
epidermal carcinoma cell line, A431. These findings indicate
that IL-10R2 is an essential component of the receptor com-
plex for IL-22 but not IL-20, which requires a different second
chain, IL-20R2 (CRF2-11), to mediate signal transduction
. The R1 chain for IL-20, IL-20R1 (zcytor7, CRF2-8), is
also distinct from that used by IL-22 . The magnitude of
STAT3 activation induced by IL-20 is consistently lower than
that induced by IL-22. Signaling through IL-20R complexes
may be less efficient than signaling through IL-22R complexes,
or A-431 cells may simply express fewer IL-20Rs than
Although IL-10R2 is required to assemble functional IL-
22R complexes, it does not directly bind IL-22 in the fluid
phase. As shown in Figure 1B, preincubation of IL-22 or IL-26
with sIL-10R2 protein did not decrease the activation of
STAT3 by either cytokine in a cell line, COLO-205, which
responds to both of these cytokines. These findings indicate
that IL-22 does not bind to the IL-10R2 chain. IL-10R2 serves
to recruit an additional kinase, Tyk2, to the receptor complex
Donnelly et al.
Class II cytokines that share the IL-10R2 chain315
. This facilitates transphosphorylation of the receptor
chains and the generation of STAT docking sites on the intra-
cellular domain of the IL-22R1 chain. Therefore, although
IL-10R2 does not participate in the initial binding of ligand, it
plays an indispensable role in signal transduction. Although
both IL-10 and IL-22 require the IL-10R2 chain for signaling,
IL-22 activates additional signaling pathways such as the
mitogen-activated protein kinase pathway, which is not acti-
vated by signaling through IL-10R complexes .
To date, no comprehensive analysis of IL-22-inducible
genes has been published; however, several IL-22-inducible
genes have been identified. IL-22Rs are expressed on a num-
ber of tissues, including kidney, pancreas, and liver . A
previous study showed that IL-22 up-regulates expression of
various acute-phase reactants in hepatocytes . These in-
clude serum amyloid A, ?1-antichymotrypsin, and haptoglo-
bin. In addition, we showed that IL-22 up-regulates expression
of the suppressor of cytokine signaling-3 (SOCS-3) gene in a
hepatoma cell line . It is noteworthy that SOCS-3 is also
highly inducible by IL-10 in monocytes .
To identify additional IL-22-inducible genes, we examined
the effects of IL-22 on gene expression by primary human
hepatocytes. Confluent cultures of freshly isolated human
hepatocytes were incubated with IL-22 (10 ng/mL) for 3 h at
37°C. RNA extracts were then prepared and analyzed by
RNase protection assay. As shown in Figure 2, IL-22 up-
regulated expression of several chemokine genes in hepato-
cytes, including IFN-inducible protein 10 (IP-10), monocyte
chemoattractant protein-1 (MCP-1), and IL-8. Although IL-10
is known to inhibit expression of IL-8 in monocytes, IL-22 did
not suppress expression of IL-8 by hepatocytes. In fact, IL-22
itself induced expression of IL-8 by hepatocytes. This indicates
that the inhibitory mechanism activated by IL-10 in monocytes
is not inducible by IL-22 in hepatocytes. The biological activ-
ities induced by IL-22 are only beginning to be defined, but it
is likely that IL-22 will be found to play a significant role in
regulating liver function. Recent studies support a potential,
therapeutic role for rIL-22 in protection against hepatitis .
THE SOLUBLE IL-22 BINDING PROTEIN
At about the same time that the IL-22R complex was being
defined, several groups identified a distinct IL-22BP [30, 33–
35]. The protein encoded by this gene (CRF2-10 or IL-22RA2)
lacks intracellular and transmembrane domains but retains the
ability to bind IL-22 with high affinity. As a result, IL-22BP
functions as a potent antagonist of IL-22 signaling by binding
IL-22 in the fluid phase and preventing its binding to the
membrane-associated IL-22R1 chain. IL-22BP is expressed at
high levels in several tissues, especially placenta and mam-
mary glands [33–35]. The high-level expression of IL-22BP in
the placenta suggests a possible role for IL-22BP in normal
placental development. IL-22BP is also expressed by DC .
The gene for IL-22BP exhibits ?34% identity to the IL-
22R1 extracellular domain. This gene is located on chromo-
Fig. 1. (A) A neutralizing anti-IL-10R2 mAb blocks
activation of STAT3 by IL-22 but not IL-20. A-431
cells were treated with IL-22 (10 ng/mL) or IL-20 (10
ng/mL) for 30 min at 37°C in the presence or ab-
sence of the anti-IL-10R2 mAb, 1A8.3 . Whole
cell lysates were then prepared, and total STAT3
protein was immunoprecipitated using a rabbit anti-
STAT3 antiserum. The levels of tyrosine-phosphory-
lated STAT3 (pY-STAT3) were then measured by
Western blotting with a phospho-STAT3-specific an-
tiserum. (B) Soluble (s)IL-10R2 does not inhibit
signaling through IL-22R or IL-26R. IL-22 (10 ng/
mL) or IL-26 (10 ng/mL) was preincubated with a
100-fold excess of sIL-10R2-Fc fusion protein (R&D
Systems, Minneapolis, MN) for 15 min at room temperature. These mixtures were subsequently incubated with COLO-205 cells for 30 min at 37°C. The
levels of tyrosine-phosphorylated STAT3 were then measured by Western blotting.
Fig. 2. IL-22 up-regulates gene expres-
sion in hepatocytes. Confluent cultures
of primary human hepatocytes (Clonet-
ics, Walkersville, MD) were treated with
IL-1 (1 ng/mL), IL-22 (10 ng/mL), or
both for 3 h at 37°C. Total RNA extracts
were prepared, and the levels of several
chemokine genes were measured by
RNase protection assay. Ltn, Lympho-
tactin; RANTES, regulated on activa-
tion, normal T expressed and secreted;
MIP-1, macrophage-inflammatory pro-
tein-1; GAPDH, glyceraldehyde 3-phos-
316 Journal of Leukocyte Biology
Volume 76, August 2004
some 6 (6q23?2) in close proximity to two other class II
cytokine receptor genes: IFN-?R1 and IL-20R1 . We re-
cently determined that IL-20R1 is in fact the primary ligand-
binding chain for IL-26, not IL-20 . Therefore, the genes
for the class II cytokines, IFN-?, IL-22, and IL-26, are clus-
tered together on chromosome 12 (12q14?3), and the genes for
the ligand-binding receptors, IFN-?R1, IL-22BP, and IL-20R1
(IL-26R1), are clustered together on chromosome 6. The gene
for IL-22R1 is located on chromosome 1 in close proximity to
the IFN-?R1 gene, and therefore, it does not localize to the
same gene cluster on chromosome 6, which encodes the other
ligand-binding proteins. Nevertheless, the close physical asso-
ciation of these two genes (IL-22R1 and IFN-?R1) suggests
that they may share some common functions.
IL-22BP specifically binds IL-22 and does not bind other
IL-10-related cytokines, including IL-10, IL-19, IL-20, IL-
24, IL-26, or IFN-?. To illustrate this specificity, we treated
A-431 cells with rhIL-20 or IL-22 in the presence of a
tenfold molar excess of purified rhIL-22BP. As shown in
Figure 3, IL-22BP blocked activation of STAT3 by IL-22
but did not block activation of STAT3 by IL-20. The affinity
of IL-22BP for IL-22 appears to be even higher than the
membrane-associated IL-22R, IL-22R1. IL-22BP inhibits
the ability of IL-22 to induce STAT activation and subse-
quent gene expression in IL-22R-positive target cells [30,
33, 34]. This suggests that IL-22BP has evolved to selec-
tively regulate IL-22 signaling.
IL-22 is coexpressed together with IFN-? and IL-26 by
activated Th1 cells, but IL-22BP does not inhibit signaling
through IFN-?Rs or IL-26R (ref.  and unpublished). IL-22,
like IFN-?, may be overexpressed in certain disease states. If
this turns out to be the case, IL-22BP might be very useful as
a therapeutic agent to block IL-22 activity. It is interesting that
IL-22 transgenic mice die within a few days after birth with
skin abnormalities that are similar to those observed in patients
with psoriasis . Moreover, subcutaneous administration of
IL-22 causes epidermal thickening and immune cell infiltra-
tion that can be neutralized by IL-22BP .
THE IL-26R COMPLEX
IL-26 (AK155) was originally identified by Knappe et al. 
as a secretory protein produced by herpesvirus saimiri-trans-
formed T lymphocytes. The gene encoding this protein was
identified by subtractive hybridization and was found to exhibit
weak but significant homology to IL-10 (?25%). IL-26 is
expressed by normal T cells and certain T cell clones following
stimulation by antigen or mitogenic lectins [23, 40]. Until very
recently, the receptor for this cytokine was unknown. However,
we determined that IL-26 signals through a novel receptor pair
consisting of the transmembrane proteins: IL-20R1 and IL-
10R2 . IL-20R1 was originally identified as one of the
components of the IL-20R complex . It is surprising that
IL-20R1 does not bind IL-19 or IL-20 with high affinity .
However, it does serve as the high-affinity, ligand-binding
chain for IL-26, and it can be argued that this protein should
actually be referred to as “IL-26R1”, as a soluble form of
IL-20R1 containing its complete extracellular domain binds
IL-26 with high affinity but does not bind IL-19 or IL-20
IL-20 is one of several IL-10-related class II cytokines that
were cloned in recent years. IL-20 signals through a het-
erodimeric receptor complex composed of IL-20R1 and IL-
20R2 . This receptor complex was originally defined based
on its ability to reconstitute IL-20 signaling in COS-7 cells
(monkey kidney fibroblasts). However, subsequent studies by
several groups showed that the IL-20R1:IL-20R2 complex can
also be used for signaling by at least two other IL-10-related
cytokines: IL-19 and IL-24 (MDA-7) [42, 43]. Therefore, this
receptor complex is shared by several cytokines, including
IL-19, IL-20, and IL-24. The shared use of receptor proteins by
several different cytokines is a recurrent feature of cytokine
signaling. For example, the common ? chain (?c) is an essential
component of at least six distinct cytokine-receptor complexes,
including those for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.
In view of its homology to IL-10, we reasoned that IL-26
might also use the IL-10R2 chain as a part of its receptor
complex. We found that neutralizing anti-IL-10R2 antibodies
can block IL-26 signaling in IL-26-reponsive target cells .
These findings indicated that IL-10R2 is a component of the
IL-26R complex. As mentioned above, IL-10R2 does not ini-
tially bind any of the IL-10-related cytokines. It participates in
ligand-receptor complex formation only after the ligand first
binds to a primary ligand-binding chain such as IL-10R1 or
IL-22R1. To identify the ligand-binding chain for IL-26, we
transfected several tumor cell lines with gene expression con-
structs encoding specific class II receptor chains, including
IL-20R1. As shown in Figure 4, forced expression of IL-20R1
in a colorectal carcinoma cell line, HT-29, enabled these cells
to respond to IL-26. IL-26 did not activate STAT3 in wild-type
HT-29 cells, but it did activate STAT3 in the IL-20R1-trans-
fected cells. These findings demonstrate that IL-20R1 is the
ligand-binding chain for IL-26 and an essential component of
the IL-26R complex. The wild-type HT-29 cells were fully
responsive to IL-22, as this cell line constitutively expresses
IL-22R1 and IL-10R2 . Like IL-22, IL-26 activates STAT3
and to a lesser degree, STAT1.
Fig. 3. The IL-22BP selectively inhibits IL-22 signaling. A431 cells were
treated for 30 min at 37°C with IL-20 (10 ng/mL) or IL-22 (10 ng/mL) in the
presence or absence of a tenfold molar excess of purified IL-22BP/Fc fusion
protein (R&D Systems). At the end of the incubation period, cell lysates were
prepared, and the levels of tyrosine-phosphorylated STAT3 (pY-STAT3) were
measured by Western blotting.
Donnelly et al.
Class II cytokines that share the IL-10R2 chain317
Activated T cells produce IL-22 and IL-26 [23, 40]. The
genes encoding IL-22, IL-26, and IFN-? are located close to
one another on chromosome 12. The close proximity of the
IL-22 and IL-26 genes to the IFN-? gene suggests that IL-22
and/or IL-26 may share certain functional activities that are
also mediated by IFN-?. Like IFN-?, IL-22 and IL-26 are
predominantly expressed by Th1 cells, suggesting transcrip-
tional coregulation of their genes. Also, as shown in Figure 2,
IL-22 induces expression of genes such as IP-10, MCP-1, and
IL-8, which are known to be inducible by IFN-? in many cell
types. Although leukocytes such as T cells and macrophages
express IL-10R2, they do not express IL-22R1 or IL-20R1
. Consequently, these cells do not respond to treatment
with IL-22 or IL-26. So far, the receptors for IL-22 and IL-26
have only been found on nonhematopoietic tissues such as
colon, liver, lung, and skin. In contrast, IL-10Rs (IL-10R1) are
only found on hematopoietic cells such as T cells and macro-
The IL-20R1 gene is not expressed in leukocytes or in
lymphoid tissues such as the spleen . We have also not
been able to detect IL-20R1 gene expression by CD14?mono-
cytes or monocyte-derived DC (unpublished). These findings
are consistent with similar findings by Wolk et al. , who
also did not detect expression of IL-20R1 by purified popula-
tions of monocytes, NK cells, B cells, or T cells. However, a
recent study indicated that IL-20 can stimulate hematopoiesis
of multipotential progenitor cells, suggesting that there is a
subset of hematopoietic cells that expresses IL-20Rs . The
IL-20R1 gene is expressed by a variety nonhematopoietic
tissues, including prostate, testis, ovary, small intestine, and
colon . We recently showed that IL-20R1 is also highly
expressed in skin and lung tissue . It is also expressed at
high levels in various brain compartments, especially the cer-
ebellum, medulla, and spinal cord. We observed that transcrip-
tion of the IL-20R1 gene gives rise to two distinct mRNA
species. These transcripts are distinguishable by Northern
blotting and display markedly different sizes: ?3.6 kb and 1.8
kb. It is likely that these mRNA transcripts represent alterna-
tive splice variants of the IL-20R1 gene. It is also possible that
the smaller mRNA species encodes a sIL-20R1 protein or a
membrane-associated form of IL-20R1 that lacks the intracel-
THE IFN-?R COMPLEX
The IFN-? gene family is composed of three distinct genes:
IFN-?1 (IL-29), IFN-?2 (IL-28A), and IFN-?3 (IL-28B) [45,
46]. The IFN-? proteins exhibit only weak homology to IL-10;
however, like IL-10, they also use the IL-10R2 chain as a
component of their receptor complex. The IFN-?R complex
consists of the unique ligand-binding chain, IFN-?R1 (also
known as IL-28R), and the accessory receptor chain, IL-10R2.
Although signaling through IL-10R, IL-22R, and IL-26R com-
plexes results predominantly in the activation of STAT3, sig-
naling through the IFN-?R complex results predominantly in
the activation of STAT1 and STAT2. These STATs together
with the accessory factor, IFN regulatory factor 9 (IRF-9; p48),
form the transcription factor complex known as IFN-stimulated
gene factor-3 (ISGF3). Activation of ISGF3 is characteristically
associated with induction of type I IFN (IFN-?/?)-responsive
The IFN-? genes are coexpressed together with other type I
IFNs (IFN-? and IFN-?) by virus-infected cells [45, 46].
Although virtually any cell type following viral infection can
express IFN-?, DC appear to be major producers of IFN-? .
Monocyte-derived DC express low levels of IFN-? when stim-
ulated with Toll-like receptor agonists such as LPS or poly I:C;
however, plasmacytoid DC (pDC) express high levels of IFN-?
following viral infection [47, 48].
In light of the fact that the IFN-? proteins activate IFN-
stimulated response elements and induce antiviral activity, we
consider these cytokines to be a novel group of “interferons”
(i.e., IFN-?1, -2, and -3) . However, another group, which
independently identified this trio of cytokines, has chosen to
refer to these proteins as “interleukins” (i.e., IL-29 and IL-28A
and -B) . Consequently, there are two distinct nomencla-
tures currently used to refer to these cytokines.
We and others showed that IFN-? signaling can be recon-
stituted in naı ¨ve target cells by forced expression of IFN-?R1
(IL-28R) and IL-10R2 [45, 46]. Similar to IL-22R and IL-26R
signaling, IFN-? signaling can be blocked by addition of
neutralizing anti-IL-10R2 antibodies. IFN-?Rs are expressed
at variable levels on most cell types; however, signaling
through IFN-?Rs is generally weaker than signaling through
type-I receptors (IFN-?/?Rs). Signaling through IFN-?Rs re-
sults in induction of many of the same genes that are induced
by signaling through IFN-?/?Rs . These include genes
such as MxA, 2?,5?-oligoadenylate synthetase, and protein
kinase R, which are believed to be important in mediating
at least some of the antiviral activities induced by type-I
Type I IFNs (IFN-? and IFN-?) are widely used as biologic
agents for treating several diseases . IFN-? is commonly
used as a primary treatment for chronic hepatitis C virus
infection and other clinical indications, including hepatitis B,
melanoma, hairy cell leukemia, and non-Hodgkin’s lymphoma.
IFN-? is used to treat multiple sclerosis. Despite the effective-
Fig. 4. Reconstitution of the IL-26R complex in HT-29 cells by forced
expression of the IL-20R1 chain. HT-29 cells were stably transfected with an
expression construct encoding the full-length IL-20R1 protein. Wild-type
HT-29 cells and IL-20R1-transfected HT-29 cells were treated with IFN-?,
IL-19, IL-20, IL-22, or IL-26 (10 ng/mL) for 30 min at 37°C. At the end of the
incubation period, cell lysates were prepared, and the levels of tyrosine-
phosphorylated STAT3 (pY-STAT3) were measured by Western blotting. CON,
318Journal of Leukocyte Biology
Volume 76, August 2004
ness of these cytokines as therapeutic agents, there are many
side-effects associated with the use of these proteins. These
adverse reactions include fatigue, fever, anorexia, myelosup-
pression, and depression. Receptors for IFN-? and IFN-? are
expressed on virtually all somatic cells, including hematopoi-
etic cells such as lymphocytes and monocytes. In contrast,
although receptors for IFN-? are broadly expressed on nonhe-
matopoietic tissues, they do not seem to be present on leuko-
cytes. This may provide a therapeutic advantage for IFN-? as
a clinical agent because treatment with this cytokine would be
less likely to cause the myelosuppression that is typically
associated with IFN-? therapy.
As discussed in this overview, there are now four distinct
cytokines that are known to use the IL-10R2 chain as a part of
their receptor complexes: IL-10, IL-22, IL-26, and IFN-?. In
fact, there are three distinct IFN-? genes: IFN-?1 (IL-29),
IFN-?2 (IL-28A), and IFN-?3 (IL-28B); so, in total, there are
actually six separate ligands that require the IL-10R2 chain for
signaling. With the exception of IL-10, the cytokines that
require the IL-10R2 chain for signaling are produced by leu-
kocytes but exert their actions on nonhematopoietic cells (Fig.
5). IL-10 is the exception because it is produced by leukocytes
(monocytes and T cells) and acts in an autocrine manner to
stimulate effector functions in leukocytes. IL-22 and IL-26 are
produced by T cells, particularly CD4?Th1 cells, but are only
active on nonhematopoietic tissues. For example, the following
tissues are known to be responsive to IL-22: skin, liver, kidney,
pancreas, colon, and lung. Similarly, IL-26 is active on skin
and lung epithelial cells as well as certain colorectal carcino-
mas but not leukocytes. Virtually any somatic cell type follow-
ing virus infection can produce IFN-?; however, DC are par-
ticularly potent producers of this cytokine. IFN-?Rs are ex-
pressed on most cell types except leukocytes.
As depicted in Figure 6, IL-10, IL-22, IL-26, and IFN-?
are initially bound by their specific ligand-binding chains
IL-10R1, IL-22R1, IL-20R1, and IL-28R1 (IFN-?R1), respec-
tively. The IL-10R2 chain is then recruited to the intermediate
complexes formed by the binding of ligand to these receptors.
Once the receptor complexes are fully assembled, the JAKs
(JAK1 and Tyk2) associated with the intracellular domains of
these receptors are activated, and they rapidly transphospho-
rylate the receptor chains on specific tyrosine residues. These
phosphotyrosines then serve as transient docking sites for
STAT transcription factors. IL-10, IL-22, and IL-26 predomi-
nantly activate STAT3 and to a lesser degree, STAT1; however,
IFN-? activates several STAT proteins, including STAT1 and
STAT2, which can combine with another cytosolic protein,
IRF-9 (p48), to form the ISGF3 transcription factor complex.
The ability of IFN-? to activate ISGF3 formation is reminiscent
of signaling by type-I IFNs and suggests that IFN-? is evolu-
tionarily related to the type-I IFNs.
The IL-10R2 chain is expressed at variable levels on virtu-
ally all somatic cells that have been examined. The one notable
exception is the brain, where the IL-10R2 chain seems to be
expressed at very low levels [38, 51]. In contrast, the ligand-
binding R1 chains for these cytokines are differentially ex-
pressed on various tissues. For example, IL-10Rs (IL-10R1)
are only expressed on hematopoietic cells such as lymphocytes
Fig. 5. The primary producers of and cellular targets for IL-10, IL-22, IL-26,
and IFN-?. IL-22 and IL-26 are produced by activated T cells and can act
upon a variety of target tissues, including kidney, liver, pancreas, and kera-
tinocytes in the skin. IL-10 is produced by T cells and monocytes and is active
only on leukocytes. IFN-? can be produced by virtually any virus-infected cell
type; however, myeloid and pDC are major producers of IFN-? as well as type-I
IFNs (IFN-? and IFN-?). IFN-?Rs are expressed on most cell types with the
notable exception of leukocytes.
Fig. 6. The IL-10R2 chain is a shared component in several class II cytokine
receptor complexes. The second chain of the IL-10R complex, IL-10R2, is a
common component of several class II cytokine receptor complexes, including
the receptors for IL-10, IL-22, IL-26, and IFN-? (IL-28/IL-29). Although the
IL-10R2 chain is broadly expressed on most cell types, expression of the
ligand-binding chains [IL-10R1, IL-22R1, IL-20R1, and IFN-?R1 (IL-28R)] is
limited to only certain cell types or tissues. Signaling through these receptor
complexes results in preferential activation of specific STATs. This in turn
results in the activation of distinct, gene-expression profiles.
Donnelly et al.
Class II cytokines that share the IL-10R2 chain319
and monocytes. They are not normally present on nonhemato-
poietic cells. IL-22 receptors (IL-22R1) are expressed on many
tissues but are particularly abundant on skin, liver, kidney,
and pancreatic cells. The ligand-binding chain for IL-26, IL-
20R1, is also expressed on many tissues; however, neither
IL-20R1 nor IL-22R1 is expressed on leukocytes . Conse-
quently, neither IL-22 nor IL-26 can exert functional activity
on leukocytes. Therefore, although T cells are major producers
of IL-22 and IL-26, they are not primary targets for these
cytokines. In contrast, many nonhematopoietic cell types ex-
press IL-22R1, IL-20R1, or both. As a result, these cells can
respond to IL-22, IL-26, or both. IL-20R1, like IL-22R1, is
expressed at high levels on epithelial cells in the skin, colon,
and small intestine. Many tumor cell lines derived from the
liver or colon express IL-22R1, IL-20R1, or both . As a
result, these cell lines are highly responsive to IL-22, IL-26, or
Class II cytokines have already proven to be useful, thera-
peutic agents for treating certain diseases . Several forms of
IFN-? are used to treat viral hepatitis and certain types of
cancer. IFN-? is used as a treatment for multiple sclerosis. The
discovery of new class II cytokines such as IL-22, IL-26, and
IFN-? provides potential, new, therapeutic agents for clinical
use. For example, the ability of IL-22 to protect against hep-
atitis in a murine model suggests a promising application for
this cytokine . At present, the potential, clinical applica-
tions for IL-26 and IFN-? are unknown, but it is expected that
phenotypic analysis of gene knockout mice will provide some
important clues to the physiological roles of these cytokines.
In addition to their potential direct effects on the growth and
function of cancer cells, these novel class II cytokines may also
be used to increase the immunogenicity of tumor cell targets.
For example, treatment of tumor cell lines with IL-22 or IFN-?
up-regulates MHC class-I antigen expression [25, 45]. This
functional activity is also known to be characteristically induc-
ible by IFN-? and IFN-? and may explain, at least in part, how
type-I IFNs promote anti-tumor cell immune responses. In-
creased expression of MHC class I and II antigens on tumor
cells is generally associated with induction of more effective
host anti-tumor cell immune responses. Therefore, these novel
class II cytokines (IL-22, IL-26, and IFN-?) may help to
promote anti-tumor cell immune responses by increasing the
ability of tumor cell targets to be recognized and killed by
effector cells of the immune system.
The content of this article does not necessarily reflect the views
or policies of the FDA, nor does mention of trade names,
commercial products, or organizations imply endorsement by
F. S. is the recipient of a Postgraduate Research Fellowship
Award from the Oak Ridge Institute for Science and Education
(ORISE) through an interagency agreement between the U.S.
Department of Energy and the Food and Drug Administration
(FDA). S. V. K. is supported in part by U.S. Public Health
Service Grant RO1 AI51139 from the National Institute of
Allergy and Infectious Diseases and by American Heart Asso-
ciation Grant AHA 0245131N. The authors thank Dr. Kevin
Moore (DNAX, Palo Alto, CA) for providing the neutralizing
anti-IL-10R2 mAb, 1A8.3.
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Class II cytokines that share the IL-10R2 chain321