The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29

Abstract

Cytokines are involved in virtually every aspect of immunity and inflammation. A cascade of responses evolves after cytokine activation, although optimal function might ultimately involve several complementary cytokines. Understanding the function of individual cytokines is complicated because their role can vary depending on the cellular source, target, and phase of the immune response. In fact, numerous cytokines have both proinflammatory and anti-inflammatory potential, with the contrasting outcome observed being determined by the immune cells present and their state of responsiveness to the cytokine. These issues make the study of cytokine biology daunting, particularly so for IL-10 and IL-10-related genes. The IL-10 superfamily is highly pleiotropic. These genes are linked together through genetic similarity and intron-exon gene structure. Significant commonality exists not only through shared receptors but also through conserved signaling cascades. However, its members mediate diverse activities, including immune suppression, enhanced antibacterial and antiviral immunity, antitumor activity, and promotion of self-tolerance in autoimmune diseases.

Full text

Update review
The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22,
IL-24, IL-26, IL-28, and IL-29
Scott Commins, MD, PhD, John W. Steinke, PhD, and Larry Borish, MD Charlottesville, Va
Cytokines are involved in virtually every aspect of immunity
and inflammation. A cascade of responses evolves after cytokine
activation, although optimal function might ultimately involve
several complementary cytokines. Understanding the function
of individual cytokines is complicated because their role can
vary depending on the cellular source, target, and phase of the
immune response. In fact, numerous cytokines have both
proinflammatory and anti-inflammatory potential, with the
contrasting outcome observed being determined by the immune
cells present and their state of responsiveness to the cytokine.
These issues make the study of cytokine biology daunting,
particularly so for IL-10 and IL-10–related genes. The IL-10
superfamily is highly pleiotropic. These genes are linked
together through genetic similarity and intron-exon gene
structure. Significant commonality exists not only through
shared receptors but also through conserved signaling cascades.
However, its members mediate diverse activities, including
immune suppression, enhanced antibacterial and antiviral
immunity, antitumor activity, and promotion of self-tolerance in
autoimmune diseases. (J Allergy Clin Immunol 2008;121:
1108-11.)
Key words: IL, cytokine, IL-10–related cytokines
Cytokines are involved in virtually every aspect of immunity
and inflammation. Not only do cytokines determine whether a
response occurs after an immune insult, the production of
particular cytokines subsequently determines the nature of the
response (cytotoxic, humoral, cell mediated, or allergic) or, in
contrast, nonresponsiveness and active immune suppression. A
cascade of responses evolves after cytokine activation, although
optimal function might ultimately involve several complementary
cytokines. Understanding the function of individual cytokines is
complicated because their role can be variable depending on the
cellular source, target, and phase of the immune response during
which they function. In fact, numerous cytokines have both
proinflammatory and anti-inflammatory potential, with the con-
trasting outcome observed being determined by the immune cells
present and their state of responsiveness to the cytokine. These
issues make the study of cytokine biology daunting, particularly
so for IL-10 and IL-10–related genes. For this review, updates in
our understanding of the extended IL-10 family will be discussed.
IL-10
IL-10 is an important immunoregulatory cytokine with multi-
ple biologic effects on different cell types. Although the primary
T-cell source for IL-10 is regulatory T lymphocytes, monocytes
and B cells are the major sources of IL-10 in human subjects.
1
IL-
10 forms a homodimer and exerts its biologic function through the
IL-10R1 and IL-10R2 receptor complex, with subsequent activa-
tion of Janus kinase (Jak) 1 and tyrosine kinase 2, signal trans-
ducer and activator of transcription (STAT) 1, and STAT3
(Table I). Other kinases, including mitogen-activated protein ki-
nase and enzymes (heme oxygenase-1) are likely also involved
in IL-10 signaling. IL-10 inhibits production of IFN-gand IL-2
by T
H
1 lymphocytes; IL-4 and IL-5 by T
H
2 lymphocytes; IL-
1b, IL-6, CXCL8 (IL-8), IL-12, and TNF-aby mononuclear
phagocytes; and IFN-gand TNF-aby natural killer cells. Mono-
cyte MHC class II molecule expression is inhibited by IL-10, as is
expression of CD23 (low-affinity IgE receptor, FceRII), intracel-
lular adhesion molecule 1, and CD80 (B7.1)/CD86 (B7.2). IL-10
inhibition of expression of the important costimulatory molecules
CD80 and CD86 by dendritic cells (DCs) and other antigen-pre-
senting cells (APCs) eliminates the ability of the APC to provide
the accessory signals necessary for T
H
cell activation. This inhi-
bition of accessory function is primarily responsible for the inhi-
bition of T
H
1 and T
H
2 cytokine production. Notably, recent
studies have also indicated that IL-10 functions directly on T cells
to inhibit their cytokine production by suppressing expression of
the T cell–costimulatory molecules CD28 and inducible T-cell
costimulator, thereby regulating their threshold of T-cell
activation.
2
Growing evidence supports a modulating role for IL-10 in
human allergic disease. Constitutive expression of IL-10 by APCs
in the respiratory tract of healthy subjects has a crucial role in the
induction and maintenance of tolerance to allergens, whereas
From the Asthma and Allergic Disease Center, Beirne Carter Center for Immunology
Research, University of Virginia Health System.
Disclosure of potential conflict of interest: J. W. Steinke has received research support
from the National Institutes of Health and the Richmond Eye & Ear Foundation.
L. Borish has received research support from GlaxoSmithKline and the National
Institutes of Health, has received honoraria from Merck & Co, and has volunteered at
the Charlottesville Free Clinic. S. Commins has declared that he has no conflict of
interest.
Received for publication January 7, 2008; revised February 19, 2008; accepted for pub-
lication February 20, 2008.
Available online April 14, 2008.
Reprint requests: Larry Borish, MD, University of Virginia Health System, Asthma and
Allergic Disease Center, Box 801355, Charlottesville, VA 22908. E-mail: lb4m@
virginia.edu.
0091-6749/$34.00
Ó2008 American Academy of Allergy, Asthma & Immunology
doi:10.1016/j.jaci.2008.02.026
Abbreviations used
APC: Antigen-presenting cell
DC: Dendritic cell
Jak: Janus kinase
STAT: Signal transducer and activator of transcription
1108

asthma and allergic rhinitis are associated with diminished IL-10
expression in the allergic airway.
3
This diminished IL-10 expres-
sion is thought to contribute to the development of an inflamma-
tory milieu, reflecting in part the presence of mature DCs. IL-10
has inhibitory effects on eosinophil survival and IL-4–induced
IgE synthesis; however, in B lymphocytes it functions as an acti-
vating factor that stimulates cell proliferation and immunoglobu-
lin secretion. IL-10 augments isotype switching to IgG4 and
functions as a growth cofactor for cytotoxic T cells. Thus IL-10
inhibits cytokines associated with cellular immunity and allergic
inflammation while stimulating humoral responses (Table II).
More detailed reviews of the biology of IL-10 can be found
elsewhere.
4,5
IL-19
IL-19 was discovered in 2000 and was found to share 21%
amino acid identity with IL-10, but as with other members of the
IL-10 superfamily, it is their similar exon-intron structure that
primarily defines their homology. Within the immune system, IL-
19 is primarily produced by monocytes, and its expression can be
induced by LPS, IL-4, and GM-CSF. IL-19 signals through a
receptor complex composed of the IL-20R1 and IL-20R2 chains
and activates monocytes in an autocrine and paracrine fashion to
release the cytokines IL-6, TNF-a, and numerous reactive oxygen
species. Monocyte IL-19 production is downregulated by IFN-g.
Roles for IL-19 have primarily been investigated in psoriasis
and allergic disorders. IL-19 is found in the suprapapillary basal
layer of healthy skin. Patients with psoriasis have increased levels
of IL-19 in basal and suprabasal keratinocytes of involved skin,
where it is thought to contribute to the inflammatory process.
Human CD8
1
T cells exposed to IL-19 induced keratinocyte
growth factor, and in a positive feedback loop, keratinocyte
growth factor–responsive elements in the IL-19 promoter increase
expression of IL-19. Cyclosporine decreases IL-19 expression,
and this might explain some of the utility of this drug in the treat-
ment of psoriasis (Table II).
IL-19 is capable of promoting T
H
2 immune deviation through
a positive feedback loop, resulting in increased numbers of IL-4–
producing and fewer IFN-g–producing cells.
6,7
Consistent with a
role for IL-19 in asthma, serum levels of IL-19 in asthmatic pa-
tients were found to be twice those of the healthy control sub-
jects and correlated with higher levels of IL-4 and IL-13 in the
serum.
6
IL-20
The human IL-20 gene maps to a 195-kb region on chromo-
some 1q32 that also includes IL-10,IL-19, and IL-24.
8
Although
part of the same family, IL-20 has diverged to a large extent from
IL-10 in sequence and function. The amino acid sequences of IL-
20 and IL-10 are only 28% identical, and the recombinant human
IL-20 protein seems to form a monomer instead of the intercalat-
ing dimer characteristic of IL-10.
8
Although multiple cell types
express IL-20, it is predominantly expressed by monocytes and
skin keratinocytes. IL-20 protein is also found at high levels in
the skin of patients with psoriasis. Overexpression of IL-20 in
mice is lethal secondary to defective skin formation. Similar to
IL-19, IL-20 signals through the IL-20R1/IL-20R2 heterodimer;
however, IL-20 also binds to the receptor complex composed of
IL-22R1 and IL-20R2 (Table I). Each of these heterodimer recep-
tor complexes functions partly through the Jak-STAT pathways.
In addition to a role in psoriasis, IL-20 has been found in higher
concentrations in synovial fluid from patients with rheumatoid ar-
thritis.
9
Other studies have also suggested a potential role for IL-
20 in atherosclerosis and angiogenesis (Table II).
10,11
IL-22
IL-22 expression is found in activated T cells and, at lower
levels, in activated natural killer cells.
12
Among T-lymphocyte
subsets, IL-22 is preferentially expressed by CD4
1
T
H
cells. No
expression of IL-22 has been found in macrophages, mature or
immature DCs, or nonimmune cells.
13
The preferential
TABLE II. IL-10 superfamily: biologic effects and clinical effect
Member Biologic effect Clinical association
IL-10 Immune suppression, anti-inflammatory Burkitt lymphoma, malignant B-cell lymphomas
IL-19 Skin development, immunoregulatory Psoriasis, asthma
IL-20 Skin development and inflammation, hematopoiesis Psoriasis, atherosclerosis, angiogenesis
IL-22 Acute-phase response, innate immunity Crohn’s disease, interstitial lung disease,
rheumatoid arthritis, psoriasis
IL-24 Proapoptosis, epidermal functions, inflammatory cascade Melanoma, psoriasis, inflammation
IL-26 Mucosal and cutaneous immunity T-cell transformation
IL-28, IL-29 Antiviral immunity Hepatitis B/C infection
TABLE I. IL-10 superfamily: receptors and signaling
Member 18Cell source Receptor Activated signal transducer
IL-10 Monocytes, B cells, regulatory T lymphocytes IL-10R1/IL-10R2 Jak1, tyrosine kinase 2, STAT1, STAT3
IL-19 Monocytes IL-20R1/IL-20R2 STAT1, STAT3
IL-20 Monocytes, skin keratinocytes IL-20R1/IL-20R2, IL-22R1/IL-20R2 Jak/STAT
IL-22 Activated T cells, activated natural
killer cells, T
H
17 cells
IL-22R1/IL-10R2 STAT3 (keratinocytes)
IL-24 Melanocytes, monocytes, T
H
2 lymphocytes IL-20R1/IL-20R2, IL-22R1/IL-20R2
(skin only)
STAT3
IL-26 Monocytes, memory T cells IL-20R1/IL-10R2 STAT1, STAT3
IL-28, IL-29 DCs IFNLR1/IL-10R2 Jak1, STAT1, 2, 3 and 5
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production of IL-22 by T cells suggests that increased levels of
this cytokine might exist in T lymphocyte–mediated diseases. No-
tably, psoriasis, Crohn’s disease, interstitial lung diseases, and
rheumatoid arthritis all have evidence of increased levels of IL-
22 protein or mRNA transcripts, and these correlate with disease
severity (Table II).
14-16
The IL-22 receptor complex is a hetero-
dimer consisting of the IL-22R1 and IL-10R2 chains (Table I).
Neither resting nor stimulated immune cells express IL-22R1,
and therefore despite its structural similarity to IL-10, immune
cells are not the target cells of IL-22. The pattern of IL-22R1/
IL-10R2 expression suggests that the most important cellular tar-
gets of IL-22 are found within the skin, kidney, respiratory, and
digestive systems. Given that these target cells are located in tis-
sues that are in contact with the environment and that IL-22 leads
to the production of antimicrobial peptides, IL-22 is presumed to
play an important role in innate pathogen defense. IL-22 also in-
duces acute-phase reactants in hepatocytes and likely possesses a
protective role in liver injury. Complicating the matter is the un-
certain role that the IL-22 binding protein, a secreted soluble de-
coy receptor, might have in modulating IL-22 effects. Another
postulated function of IL-22 binding protein includes temporary
sequestration of IL-22 to prolong its half-life, possibly facilitating
the arrival of IL-22 at remote parts of the body.
IL-24
Originally identified as a tumor suppressor molecule (mela-
noma differentiation-associated gene 7) that was expressed in
healthy melanocytes but not metastatic melanoma cells, mela-
noma differentiation-associated gene 7 was subsequently discov-
ered to have a chromosomal location within the IL-10 locus with
which it shares structural and sequence homology and is now
termed IL-24. It is produced by monocytes and T
H
2 lymphocytes
in an IL-4–inducible fashion. IL-24 signals through a heterodimer
consisting of the IL-20R1 and IL-20R2 chains, leading to activa-
tion of STAT3 (Table I). IL-24 promotes secretion of TNF-aand
IL-6 from human monocytes. Its potential role as a cancer thera-
peutic is derived from evidence that IL-24 induces antitumor im-
mune responses with significant independent ‘‘bystander’’
antitumor effects (Table II).
17,18
In addition, IL-24 promotes ap-
optosis of tumor cells without apparently targeting nonneoplastic
tissue. Jak/STAT activation is not involved in apoptotic signaling
because Jak/STAT knockout mice still demonstrate apoptosis of
tumor cells after exogenous IL-24 addition. Current investiga-
tions are focused instead on the unique expression of the intracel-
lular chaperone molecule GRP78/BiP by cancerous cells, which
might play a role in their susceptibility to apoptosis. Given the ap-
parently ubiquitous apoptotic effect on malignant cells, the lack
of an effect on normal cells, and the absence of significant side ef-
fects (eg, cytokine storm), IL-24 is a potentially important candi-
date cancer therapeutic, and early-phase I/II studies have shown
promise.
IL-26
In contrast to IL-19,IL-20, and IL-24,IL-26 is located on chro-
mosome 12q15, where it clusters with IL-22 and IFN-g. IL-26
is primarily generated by monocytes and memory T cells. It is
considered important in the transformation of human T cells after
their infection by herpes virus saimiri.
19
The herpes virus saimiri/
IL-26 interaction exhibits shared features with the role of the
similar herpesvirus, EBV, in B-cell transformation. Similar to
IL-10, IL-26 forms homodimers. IL-26 has a unique receptor con-
sisting ofa heterodimer of the IL-20R1 chain and theIL-10R2 chain
(Tab le I).
20
Binding of the IL-26 receptor leads to phosphorylation
of both STAT1 and STAT3 and induction of CXCL8 (IL-8), IL-10,
and intracellular adhesion molecule 1 (ICAM-1).
IL-28 AND IL-29
IL-28A and IL-28B, alternatively named IFN-l2 and IFN-l3,
belong, with IL-29 (IFN-l1), in a new cytokine family that shares
with type I IFNs the same Jak/STAT signaling pathway. IFN-ls
exhibit several common features with type I IFNs, including
antiviral, antiproliferative, and antitumor activities. Despite sig-
nificant amino acid homology with type I IFNs, the intron-exon
structure of the IFN-lfamily genes more closely resembles that
of IL-10.
21
Moreover, IFN-ls act through a cell-surface receptor
composed of 2 chains, one being IFN-lspecific (IFN-lR1) and
the second, IL10R2, being shared among IL-10, IL-22, and IL-
26. The gene encoding IFN-lR1 is located on human chromo-
some 1, which is in close proximity to the gene encoding the
IL-22 receptor. In addition to the mRNA encoding the full-length
IFN-lR1, 2 splice variants have been identified in human cells.
21
One variant encodes a receptor with a deletion of 29 amino acids
in its intracytoplasmic portion, likely disabling its signaling ca-
pacity, thus suggesting decoy function. The second variant en-
codes only the ectodomain, which is likely a secreted (soluble)
receptor.
21
The ratio of the 2 receptor variants will determine
whether a given cell signals in response to the cytokine.
Although IL-10R2 is ubiquitously expressed, IFN-lR1 appears
to be more tightly regulated. The mRNA encoding IFN-lR1 is
undetectable in fibroblast and endothelial cells.
21
Monocytes
freshly isolated from human blood do not express IFN-lR1, but
its expression can be induced when they differentiate into DCs af-
ter IL-4 and GM-CSF treatment. IFN-lR1 is expressed in cell
lines from various tumors. Initial work showed that all IFN-lsub-
types were induced on infection of HeLa, HuH7, or HT29 cell
lines by Dengue virus, Sindbis virus, vesicular stomatitis virus,
or encephalomyocarditis virus supporting a role in antiviral im-
munity.
21,22
Subsequent work has shown that other viruses are
also capable of inducing IFN-lexpression.
Similar to type I IFNs, IL-28 and IL-29 (IFN-ls) induce the
activation of the Jak/STAT signaling pathways that variously lead
to phosphorylation of STAT1, STAT2, STAT3, STAT4, and
STAT5.
22-24
Jak1, in particular, has been shown to be critical in
mediating IFN-l–induced STAT phosphorylation.
23
Evidence
suggests that STAT2 is the crucial STAT in establishing type I
IFN activity because it is specifically recruited in the cascade
leading to IFN-stimulated response element promoter activity.
25
IFN-linduces homodimers of STAT2 capable of recognizing
both the IFN-stimulated response element and IFN-gactivation
site sequences. It is therefore not surprising that many genes
whose expression is classically induced by both type I IFNs and
IFN-gare also induced by IFN-ls. One notable difference be-
tween IFN-land type I IFNs is that IFN-lshifts immature DCs
toward a program characterized by the ability to produce
Foxp3-expressing CD4
1
CD25
1
regulatory T cells. In fact, recent
studies performed with a mixed lymphocyte reaction show that
IFN-l–treated DCs induce IL-2–dependent proliferation of
CD4
1
CD25
1
Foxp3
1
innate regulatory T cells. Hence IFN-ls
are able to generate tolerance-inducing DCs.
26
By definition, an IFN must be able to ‘‘interfere’’ with viral
replication. As discussed above, IFN-lindeed exhibits antiviral
J ALLERGY CLIN IMMUNOL
MAY 2008
1110 COMMINS, STEINKE, AND BORISH

activities. Of note, IFN-linhibits hepatitis B and C virus
replication (Table II).
27
This observation could be important be-
cause IFN-lmight be an alternative to IFN-afor the treatment
of HCV-infected patients displaying resistance to IFN-a, espe-
cially if their resistance is due to type I IFN dysfunction.
28
Data
from recent studies suggest that the in vivo antiviral activity of
IFN-lis exerted on the immune system rather than preventing
the cells from becoming infected.
29
Moreover, IFN-ls exert an
in vivo antitumor effect similar to that of type I IFNs that is likely
mediated by an action on tumor immune surveillance rather than
through its antiproliferative activity on tumor cells.
30
To date,
there is no described phenotype associated with defective IFN-
lproduction on signaling except one single nucleotide polymor-
phism in the gene encoding IFN-lR1 that might be associated
with susceptibility to allergic rhinitis.
31
CONCLUSION
The IL-10 superfamily is highly pleiotropic. Its members are
linked together through genetic similarity and intron-exon gene
structure. Significant commonality exists not only through shared
receptors but also through conserved signaling cascades. How-
ever, its members mediate diverse activities, including immune
suppression, enhanced antibacterial and antiviral immunity, an-
titumor activity, and promotion of self-tolerance in autoimmune
diseases.
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