ARTICLE
Auteur(s) : Katia Boniface1, Jean-Claude
Lecron1, François-Xavier Bernard2, Guy
Dagregorio3, Gérard Guillet4, François
Nau1, Franck
Morel1
1Laboratoire Cytokines et Inflammation, UPRES-EA
3806, CHU de Poitiers, Université de Poitiers, 40 Avenue du Recteur
Pineau, 86022 Poitiers, France
2BIOalternatives, 1 bis rue des Plantes,
86160 Gençay, France
3Service de Chirurgie Plastique, CHU La Milétrie,
86022 Poitiers, France
4Service de Dermatologie, CHU La Milétrie,
86022 Poitiers, France
Cytokines induce and control hematopoiesis, as well as immune and
inflammatory responses. They are also key factors in the cross talk
between the immune system and other systems including hepatic,
nervous, cardiac and cutaneous systems, leading to an adaptive and
integrated response of the organism to stress. The regulation of
cytokine production is essential for homeostasis, and a
dysregulation of cytokine production can lead to the development of
pathologies. Th1 cells, through their production of interferon γ
(IFN-γ), are critical for the eradication of intracellular
pathogens, but can also cause inflammatory pathologies. Th2 cells
by contrast, are important for the regulation of responses to
parasites, but the associated production of interleukin (IL)-4,
IL-5 and IL-13 can promote allergic manifestations. Cytokines
directing Th1 and Th2 responses, produced by the respective T cell
subsets, have been shown to cross-regulate each other’s development
and function. Regulatory T cells represent another
subpopulation of T lymphocytes with immunosuppressive properties
that mainly produce transforming growth factor β (TGF-β) and IL-10
and are involved in the generation and maintenance of immune
tolerance.Effective immune responses against pathogens are
sometimes accompanied by strong inflammatory reactions. To minimize
damage to self, the activation of the immune system also triggers
anti-inflammatory processes. Both inflammatory and
anti-inflammatory reactions are normal components of the immune
response, which fight infections while preventing immune pathology.
Among the anti-inflammatory cytokines, IL-10 is one of the most
important and is produced by a large number of immune cells.In this
review, we will discuss current knowledge about the effects of the
IL-10 family of cytokines on keratinocytes and the cutaneous
system, and their potential role in psoriasis.
IL-10-related cytokines
IL-10 was identified in 1989 as a “cytokine synthesis inhibitory
factor”, and its biological activities are now well defined [1, 2].
Since 1995, five cytokines, structurally related to IL-10, have
been described and presently form this family of cytokines: IL-19,
IL-20, IL-22, IL-24 (melanoma differentiation-associated gene
mda-7) and IL-26 (AK-155) [1, 3-9]. They are mainly produced by
immuno-hematopoietic cells and act through heterodimeric receptors
belonging to the type II cytokine receptors family ( (figure 1) ).
IL-10 mediates its biological activities through the
IL-10R1/IL-10R2 receptor [10-12]. The IL-10R2 chain is also a
component of the IL-22 receptor, together with the IL-22R1 subunit
[5, 13], and of the IL-26 receptor, in association with the IL-20R1
chain [14]. In contrast to the other subunits, IL-10R2 is
ubiquitously expressed in the organism. Consequently, the spectrum
of action of IL-10, IL-22 and IL-26 is restricted by the expression
pattern of IL-10R1, IL-22R1 and IL-20R1 chains, respectively. The
IL-10R1 subunit is mainly detected in lymphoid tissues and immune
cells [2, 15, 16], but a weak expression is also observed in skin,
pancreas and liver [15]. IL-22R1 is strongly expressed in pancreas
and, at lower levels, in skin, colon, small intestine and liver,
whereas it is not detected in immuno-hematopoietic cells [15, 17-19
and unpublished results].
The sharing of one or two receptor subunits is frequent in this
family of cytokines. Indeed, IL-19, IL-20 and IL-24 act through the
IL-20R1/IL-20R2 receptor [4, 20]. IL-20 and IL-24 also bind the
IL-22R1/IL-20R2 complex [8, 20, 21]. Although IL-20R1 and IL-20R2
subunits are all expressed in skin, pancreas and liver, only weak
expression of IL-20R2 has been detected in immune cells, and
IL-20R1 not at all [15, 16, 22].
The common use of receptors subunits explains, in part, the
induction of the same signaling pathways. Indeed, the binding of
IL-10-related cytokines to their receptors activates the Janus
kinase (JAK) and signal transducers and activator of transcription
(STAT) pathway; in particular STAT3 [4, 11, 13, 20, 23-25]. IL-22
and IL-24 have also been reported to activate the MAP-kinase
pathway [26-28].
Mainly produced by monocytes, macrophages, B and T cells,
IL-10 is a multifunctional cytokine with diverse effects on most
hematopoietic cells [2]. It inhibits the antigen-presentation
capacity of macrophages and dendritic cells (DC) [29-32], and the
proliferation of CD4+ T cells [33, 34]. IL-10
strongly inhibits cytokine production such as IL-2 synthesis by
T cells [35] and the synthesis of the pro-inflammatory
cytokines IL-1β, IL-6, tumor necrosis factor α (TNF-α), monocyte
inflammatory protein-1α (MIP-1α), RANTES, IL-8 and eotaxin by
monocytes/macrophages [36, 37]. In addition, IL-10 also increases
the expression by activated monocytes of several anti-inflammatory
proteins, such as IL-1 receptor antagonist, soluble TNF-α receptor
and tissue inhibitor of matrix metalloproteinases [2]. These
properties contribute to the immunosuppressive and
anti-inflammatory activities of IL-10. In contrast, it stimulates
Th2 cell differentiation via the inhibition of IFN-γ secretion by
activated T cells [38]. This cytokine also directly activates
B cells proliferation and differentiation, promotes the switch
toward IgG1, IgG3, and in combination with TGF-β, toward IgA1 and
IgA2 [2].
In contrast to the anti-inflammatory functions of IL-10, other
IL-10-related cytokines are mostly described for their
pro-inflammatory activities.
IL-19 is produced by resting and LPS- or granulocyte
macrophage-colony stimulating factor-activated monocytes and, at
lower level, by B cells [3, 15]. IL-19 induces inflammatory
responses by stimulating the expression of IL-6 and TNF-α in
monocytes. It also induces the apoptosis of mouse monocytes and the
production of reactive oxygen species [39]. IL-19 has also been
reported to promote Th2 responses. In human peripheral blood
mononuclear cells (PBMC) stimulated with concanavalin A, IL-19
increases IL-4, IL-5, IL-10, IL-13 and IL-19 secretion, and
decreases those of IFN-γ [40-42]. It also up-regulates the
expression of keratinocyte growth factor (KGF) transcripts by
CD8+ T cells [43]. High IL-19 serum levels are
observed in patients with asthma as compared to healthy controls,
suggesting a role in the pathogenesis of asthma [42].
IL-20 is produced by keratinocytes, glial cells and activated
monocytes [4, 15, 44], and was first described for its
pro-inflammatory activity in skin [4]. IL-20 stimulates the
expression of KGF transcripts by CD8+ T cells [45],
increases formation of multipotential hematopoietic progenitor
cells [46] and inhibits angiogenesis through the COX-2 regulatory
pathway [47].
IL-22 is mainly expressed by activated T cells, mast cells
and NK cells [6, 15]. Despite initial controversy, neither resting
nor activated immune cells express the IL-22R1 chain, which
explains why IL-22 has no effect on hematopoietic cells [5, 15, 18,
48]. IL-22 is involved in the regulation of inflammation in several
tissues, including liver [49], pancreas [50], intestine [19] and
skin [17, 48], where it up-regulates the expression of
pro-inflammatory proteins. In rheumatoid arthritis, IL-22 induces
the proliferation of synovial fibroblasts and the production of
monocyte chemoattractant protein-1 (MCP-1) by these cells, thereby
promoting inflammatory responses [51]. In contrast, IL-22 has a
protective effect in murine models of liver injury. Moreover, IL-22
overexpression in the human hepatocellular carcinoma HepG2 cell
line promotes cell survival and growth, via the activation of STAT3
[52]. These biological activities of IL-22 are antagonized by the
IL-22 binding protein (IL-22BP) soluble receptor, which binds IL-22
and prevents its interaction with the membrane receptor [53-55].
IL-22BP mRNA is expressed by monocytes, activated B cells and
epithelial cells. Tissue expression studies showed a high
expression of IL-22BP mRNA in placenta, spleen, skin, and lung, and
at lower levels in heart, pancreas and prostate [55].
IL-24 was originally identified as mda-7, a molecule strongly
up-regulated following differentiation of the human melanoma cell
line HO-1 [7, 8]. This cytokine is expressed by melanocytes [7], by
PBMC activated with concanavalin A [8, 15, 56], phytohaemagglutinin
[56] or IL-4 and LPS [57], and by some differentiation
inducer-treated tumor cell lines [58]. IL-24 induces growth arrest
or apoptosis of a large panel of cancer-derived cells, without
affecting normal cells [27, 59-65] and as IL-20, inhibits
angiogenesis [66]. Interestingly, its expression is inversely
correlated with melanoma progression [59, 67]. IL-24 is currently
in human Phase I/II clinical trials as a potential anti-cancer
drug, through adenovirus-mediated gene therapy [68, 69].
Intratumoral injection of an adenovirus containing the IL-24 gene
in patients with advanced cancer results in elevated IL-24
expression and tumor cells apoptosis [68, 69]. IL-24 also activates
IL-6, TNF-α and IFN-γ production by PBMC, suggesting its
involvement in inflammation [56].
First designated as AK155, IL-26 was cloned as a protein
expressed by herpes virus saimiri-transformed T cells [9].
IL-26 is also expressed by activated NK and T cells,
particularly type 1 cells [15]. The only IL-26 activity described
so far is the induction of IL-8 and IL-10 secretion by the Colo205
carcinoma cell line [14].
Involvement of the IL-10-related cytokines in skin biology
Recently, a growing number of reports have described the
implication of IL-10 and its related cytokines in the biology and
function of the skin.
IL-10
IL-10 appears to be implicated in the regulation of the cutaneous
inflammatory response of wound healing. IL-10 expression is rapidly
up-regulated after skin incision [70, 71]. It inhibits the
infiltration of neutrophils and macrophages in the injured tissue
and down-regulates the expression of pro-inflammatory cytokines
(IL-1β, IL-6, TNF-α) and chemokines (MCP-1, MIP-1α) [71]. Despite
preliminary results suggesting a direct action of IL-10 on
keratinocytes, the lack of IL-10R1 expression and STAT3
phosphorylation in response to IL-10 suggest an indirect effect on
these cells. This is reinforced by the absence of any biological
effect of IL-10 on unstimulated or stimulated normal human
epidermal keratinocytes or on the HaCat keratinocyte cell line [17,
72-75].
IL-10 is produced by skin-infiltrating activated T cells
(unpublished results), but there are controversial data concerning
IL-10 synthesis by keratinocytes. Some studies showed that IL-10
production by keratinocytes depends on the differentiation state
and is induced by ultraviolet radiation in vitro and in vivo
[76-78]. In contrast, we and other groups failed to detect any
IL-10 mRNA in epidermal keratinocytes or in the HaCat cell line
[79, 80]. In any case, IL-10 expression is up-regulated in skin
samples from Th2 pathologies such as atopic dermatitis, melanoma
and lymphomas [81-83], whereas a relative deficiency is found in
psoriasis, a Th1 disease [84]. These data suggest that IL-10 may
indirectly down-regulate keratinocyte inflammatory responses and
may thus participate in the regulation of the skin immune
network.
IL-20
Skin appears to be a main target for IL-20. Overexpression of IL-20
in transgenic mice causes neonatal lethality with skin
abnormalities, including a thickened epidermis, hyperkeratosis and
compact stratum corneum, indicating an aberrant epidermal
differentiation [4]. The expression of cytokeratin (CK)5, CK6 and
CK14, associated with keratinocyte proliferation, is increased.
However, the expression of the differentiation markers filaggrin
and loricrin are not altered. These perturbations appear to be
caused by circulating IL-20, since the same phenotype is observed
in mice expressing the transgene in skin, and also in liver and the
lymphoid lineage. In the HaCat cell line, IL-20 stimulates the
activation of STAT3 and induces the expression of genes involved in
inflammation, such as TNF-α, S100A8 and MCP-1 [4].
IL-22
Epidermal keratinocytes, as well as the keratinocyte cell lines
HaCat and SVK14, express the two chains of the IL-22 receptor, i.e.
the IL-10R2 and IL-22R1 subunits [17, 48], whose expression is
up-regulated by IFN-γ, but not IL-4 [48]. The binding of IL-22 to
its receptor induces the phosphorylation of STAT3 in these cells
[17, 48]. Using a cDNA array screening approach, we have
demonstrated the involvement of IL-22 in skin inflammatory
processes [17]. In epidermal keratinocytes, IL-22 up-regulates, in
a dose- and time-dependent manner, the expression of
S100A7-psoriasin, S100A8 and S100A9 transcripts, known for their
pro-inflammatory activities. Interestingly, the expression of these
proteins is up-regulated in psoriasis [85]. Moreover, IL-22
strongly induces the hyperplasia of in vitro reconstituted human
epidermis, resulting mostly from an inhibition of keratinocyte
differentiation. Indeed, IL-22 down-regulates the expression of
CK10, involucrin, loricrin and filaggrin, all associated with
keratinocyte differentiation, whereas it has no effect on
keratinocyte proliferation. Finally, IL-22 induces keratinocyte
migration in an in vitro wound-healing model [17].
In parallel, Wolk et al. showed that in epidermal keratinocytes,
IL-22 up-regulates, in a time- and dose-dependent manner, the
expression of human β-defensin 2 and β-defensin 3 mRNA, but not
that of β-defensin 1. This induction depends on keratinocyte
differentiation since an elevated calcium concentration promotes
the IL-22-induced β-defensin expression [48]. In addition, IL-22
induces the transcription of S100A7-psoriasin [17, 48], recently
shown to confer resistance to skin infection by Escherichia coli
[86]. High levels of IL-22 are associated with strongly
up-regulated β-defensin expression in skin from patients with
psoriasis and atopic dermatitis [48]. These data suggest that IL-22
is a T cell-derived cytokine that promotes the cutaneous innate
immune response and plays an important role in skin inflammatory
processes.
IL-19, IL-24 and IL-26
Normal epidermal keratinocytes express the IL-20R1, IL-20R2,
IL-10R2 and IL-22R1 receptor chains, suggesting that they could be
a potential target for IL-19, IL-24 or IL-26. In the HaCat cell
line, the phosphorylation of STAT3 in response to IL-24 or IL-26,
together with an increased secretion of IL-8 in response to IL-26,
have been reported [8, 24, 87], suggesting a role for these two
cytokines in skin inflammatory responses. Furthermore, the
expression of the c49a gene, which exhibits high homology with
IL-24, is increased during wound repair in rat [88]. Finally, no
biological activities of IL-19 have been reported on keratinocytes
so far.
Taken together, these data show that keratinocytes are potential
targets for the cytokines of the IL-10 family, except for IL-10
itself. In order to compare the biological activity of these
IL-10-related cytokines in the same in vitro assay, we performed
microarray analysis on cytokine-stimulated normal human epidermal
keratinocytes. A differential gene expression profile between
cytokine-treated and control cultures is shown in ( figure 2A ). In these
culture conditions, IL-22 was able to modify the expression of 9
genes out of 154, as compared to 6 for IL-24, 2 for IL-20 and 0 for
IL-10, IL-19 and IL-26. This was confirmed by real-time RT-PCR
experiments, where IL-22 and, to a lesser extent, IL-24 and IL-20
are shown to down-regulate the expression of the CK10 gene (a
differentiation marker) and up-regulate those of the S100A7 gene
(an inflammation marker) and the β-defensin 2 gene (an innate
immunity marker) ( (figure 2B) ). As
expected, IL-10 had no effect on epidermal keratinocytes. Finally,
IL-19 and IL-26 did not significantly modify the keratinocyte gene
expression profile analyzed in our experiment. In agreement with
these results, we showed that IL-22, IL-24, and, to a lesser
extent, IL-20, are able to induce STAT3 phosphorylation in
epidermal keratinocytes ( (figure 2C) ). This is
of great interest since STAT3 has been shown to be important for
skin homeostasis [89, 90]. A weak STAT3 activation is observed in
response to IL-19 and IL-26, whereas IL-10 has no effect. The study
of the receptor subunit expression showed that normal epidermal
keratinocytes express IL-22R1, IL-10R2 and IL-20R2 mRNA, whereas
IL-20R1 mRNA is only weakly detected in all three keratinocyte
samples tested ( (figure 2D) ). Taken
together, these results could explain the limited effect of IL-19
and IL-26 on STAT3 activation and suggest that IL-20 and IL-24 act
mainly through the IL-22R1/IL-20R2 receptor in epidermal
keratinocytes.
The observations that some IL-10-related cytokines induce in
keratinocytes a gene expression profile and a morphology resembling
psoriatic lesions, together with the human psoriasis-like phenotype
of transgenic mice expressing a constitutive active form of STAT3,
led us to consider the putative role of these cytokines in the
pathophysiology of psoriasis.
IL-10-related cytokines and psoriasis
Psoriasis: an auto-immune-mediated disease
Psoriasis is one of the most common cutaneous inflammatory
pathologies, affecting 2.5 % of the world’s population. The
cause of psoriasis is still unknown, but seems to result from both
genetic predispositions and environmental factors (stress,
infections…). Plaque-psoriasis is the most widespread clinical type
of this disease and is characterized by scaling, reddened and
indurated skin lesions derived from excessive growth of skin
epithelial cells [91]. Psoriasis is a cell-mediated disease
characterized by a thickened epidermis resulting from a
hyperproliferation and an abnormal differentiation of
keratinocytes, accompanied by vascular hyperplasia and inflammatory
immune cell infiltrates at the lesion site. The pathogenesis of
this disease depends on the activation of immune cells, including
T cells, DC, neutrophils, macrophages, mast cells, and on the
increased production of pro-inflammatory mediators such as
cytokines, chemokines and growth factors [92]. Immune cells
infiltrated within psoriatic skin secrete large amounts of type 1
cytokines, such as IFN-γ and TNF-α, which play a primary role in
the pathogenesis of psoriasis [93]. TNF-α is mainly produced by
lesional DC, macrophages and T cells that enhance local
inflammation, DC activation and maturation [94]. IFN-γ, produced by
both CD4+ and CD8+ T cells, has a major
role in psoriasis too, since subcutaneous injection of IFN-γ has
been shown to induce psoriasis in normal skin at the injection site
in 10 out of 42 psoriatic patients [95]. Moreover, IFN-γ and TNF-α
induce keratinocytes to release pro-inflammatory cytokines such as
IL-6, IL-7, IL-8, IL-12, IL-15, IL-18 and TNF-α [96]. Other
cytokines highly expressed and potentially involved in psoriatic
pathogenesis are IL-1, IL-8, IL-15, IL-18 and IL-12 family members
[97-101]. In contrast, nil or low expression of IL-4 and IL-10 Th2
cytokines has been reported in psoriatic lesions [102, 103].
Participating in the recruitment of immune cells to the skin during
inflammation are chemokines produced by keratinocytes and/or by
inflammatory infiltrates, such as CCL4, CCL17, CCL20, CCL22, CCL27
and CXCL10 [104, 105]. The increased expression of growth factors
such as TGF-α, KGF and vascular endothelial growth factor may
contribute to changes in angiogenesis [94, 106].
This immune cellular infiltrate, accompanied by a complex
network of cytokines, chemokines and growth factors, leads to
abnormal keratinocyte proliferation and differentiation as well as
altered angiogenesis.
Cytokines of the IL-10 family and psoriasis
Involvement of IL-10 in psoriasis development
In the context of a biased Th1/Th2 balance, conflicting data
regarding IL-10 expression in psoriasis have been reported. IL-10
mRNA is either undetected or detected at low levels in lesional
psoriatic skin [102, 103], but in any case at lower levels than
found in atopic dermatitis and mycosis fungoides [84].
Interestingly, conventional anti-psoriatic treatments are
associated with enhanced IL-10 and decreased IFN-γ production by
PBMC, suggesting that IL-10 may have anti-psoriatic activity [84,
107]. Consequently, therapeutic effects of recombinant IL-10 in
psoriatic patients have been studied in several clinical trials.
The first pilot trial conducted by Asadullah et al. in 1998 showed
that subcutaneous treatment with IL-10 leads to a partial or
complete disappearance of psoriatic plaque [84]. Phase II clinical
trials confirmed that subcutaneous administration of IL-10 is well
tolerated and leads to a diminution of the psoriatic area and
severity index. In parallel, an improvement of histological
parameters, a decreased cutaneous cell infiltration, a decreased
lesional expression of IFN-γ, TNF-α, IL-17, IL-8 and CXCR2 and of
the systemic type 1/type 2 cytokine ratio have been reported [108,
109]. However, the clinical improvement diminishes after 6 to 8
weeks during the course of a 12-week clinical trial, despite a
sustained systemic decrease of type 1 cytokine production [110].
Finally, a phase II clinical trial in patients with chronic plaque
psoriasis in remission showed that IL-10 treatment decreased the
incidence of relapse [111].
Overall, clinical and biological data generated by these trials
demonstrate that IL-10 therapy is well tolerated and is able to
target immune cells such as T cells and dendritic cells. The
anti-psoriatic activity of IL-10 is likely to be mediated by the
impaired antigen presenting properties of DC and/or by the direct
inhibition of type 1 cytokine production by Th1 cells. A direct
effect of IL-10 on keratinocytes is unlikely since these cells do
not express the IL-10R1 chain [17, 73]. However, the expression of
the IL-10R2 chain suggests its association with others partners
such as IL-20R1, IL-20R2 and IL-22R1 chains, present on
keratinocytes, rendering these cells susceptible to the action of
IL-19, IL-20, IL-22, IL-24 and IL-26. Since all these cytokines are
linked to a pro-inflammatory gene expression profile, their
relative involvement in the pathogenesis of psoriasis has been
studied.
Expression of the IL-10-related cytokines and their receptors
in psoriatic skin
IL-19 and IL-20 mRNA are expressed focally in the epidermis of
about 80% of untreated psoriatic patients, and their expression is
confined to the basal and suprabasal keratinocyte layers of
lesional skin [112]. A careful analysis excluded
monocytes/macrophages, lymphocytes, endothelial and dendritic
Langerhans cells as sources of IL-19 and IL-20 mRNA. In contrast,
IL-24 mRNA is expressed exclusively in the dermal compartment, in
mononuclear inflammatory cells. Interestingly, the expression of
IL-19, IL-20 and IL-24 mRNA is not detected in non-lesional skin of
psoriatic patients [112]. Immunohistochemical studies confirmed
that psoriatic skin expresses higher levels of IL-19 and IL-20
protein than healthy skin. However, in contrast to IL-19, whose
expression remains confined to basal keratinocytes in psoriasis,
IL-20 is overexpressed in the whole psoriatic epidermis [45].
Interestingly, after 4 weeks of treatment with either cyclosporine
A or calcipotriol, both IL-19 and IL-20 mRNA disappear, correlating
with changes in clinical and histological scores [112]. Such a
decrease of IL-19 mRNA expression is also observed in IL-4-treated
psoriatic patients, in parallel with a reduced IL-8 production and
IFN-γ/IL-4 ratio, whereas IL-20 remains unchanged [113]. These data
suggest that IL-19 and IL-20 are keratinocyte-derived
pro-inflammatory signal mediators, linked to the presence of
autoreactive Th1 cells in psoriatic skin lesion. However, the
persistence of IL-20 in IL-4-treated patients suggests that IL-19
and IL-20 expression is differentially regulated in psoriasis.
Based on in vitro data, IL-22 also represents a good candidate
as a major T cell-derived pro-inflammatory cytokine able to induce
a psoriasis-like phenotype. Indeed, Wolk et al. and our group
reported an increased expression of IL-22 mRNA in lesional skin of
psoriatic patients [48 and unpublished results]. Even though
skin-infiltrating T cells are good candidates,
characterization of the IL-22-producing cells and potential
regulation of IL-22 production need to be studied in more
details.
In parallel, the expression of the receptors of these cytokines
has been studied in psoriatic skin lesions. Blumberg et al. first
described the up-regulated expression of IL-20R1 and IL-20R2 mRNA
in keratinocytes, as well as endothelial and mononuclear cells in
psoriatic lesions compared to the very low levels detected in
healthy skin [4]. Romer et al. confirmed mRNA expression of these
receptor chains throughout the psoriatic epidermal layer, whereas
IL-22R1 mRNA is predominantly detected in the superficial part of
the psoriatic epidermis. A similar, but weaker expression pattern
for IL-20R1, IL-20R2 and IL-22R1 chains is detected in uninvolved
psoriatic skin [112]. This up-regulated expression of IL-20R1 and
IL-20R2 is also observed at the protein level [45]. Interestingly,
mRNA levels for IL-20R1, IL-20R2 and IL-22R1 are not affected by
cyclosporine A, calcipotriol or IL-4 treatment [112, 113].
Possible relations between the polymorphisms of IL-10, IL-19,
IL-20 and IL-24 and psoriasis
Human gene polymorphism has been shown to play a role in immune
responses. Some polymorphisms of cytokines and cytokine receptors
may have direct functional significance by altering the level of
gene expression and/or its function. The relevance of IL-10 gene
polymorphisms has been demonstrated in numerous immune inflammatory
diseases including rheumatoid arthritis, inflammatory bowel disease
and asthma. The positive association of the IL-10.G13 allele with
familial psoriasis has been reported, suggesting that the IL-10
locus contributes to the heritability of psoriasis susceptibility
[114, 115]. Kingo et al. analyzed three single-nucleotide
polymorphisms in the IL-10 5′ flanking region in patients with
plaque-type psoriasis and in healthy volunteers. The IL-10 ACC
haplotype is associated with lower activity of the disease, and ATA
haplotype with persistent eruption [114]. As ATA is related to low
IL-10 secretion [116], differences in IL-10 secretion level might
contribute to the differences in the clinical course of psoriasis.
Associations between IL-19, IL-20 and IL-24 polymorphisms and
psoriasis have also been assessed. Minor alleles of the IL-19 gene
revealed a protective effect as regards psoriasis, but combined
haplotype analysis of the IL-19 and IL-20 genes demonstrated that
the protective effect of the IL-19 gene is secondary to the
susceptibility effect of the IL-20 gene [117, 118]. While the
IL-19/IL-20 haplotype CACCGGAA is a susceptibility factor for
psoriasis [118], a significant protective effect of the combined
haplotype CAAAC of the IL-20 and IL-24 genes against plaque-type
psoriasis has been established [119]. Nevertheless, family-based
studies are required to confirm the implication of IL-19, IL-20 and
IL-24 genes in the predisposition for psoriasis. Furthermore,
studies concerning the effects of these haplotypes on the
expression levels of IL-19, IL-20 and IL-24 are needed.
These observations have expanded the pro-inflammatory cytokine
field surrounding lesional psoriatic skin. Obviously, the
expression of a number of cytokines of the IL-10 family is enhanced
in psoriasis. Up-regulated expression of the corresponding
receptors on psoriatic keratinocytes indicates that these cytokines
may play a central role in the epidermal inflammation. In vivo
studies showed that transgenic mice overexpressing IL-20 have a
thickened epidermis, hyperkeratosis and a compact stratum corneum,
which resembles psoriasis [4]. In vitro data demonstrated that
IL-22 is able to induce a “psoriasis-like” gene expression profile
and phenotype [17]. Based on genomic screening approaches, we have
highlighted the predominance of biological activities of
keratinocyte IL-22 and IL-24 over IL-19, IL-20, and IL-26. However,
action on other skin cells should not be ignored. Likewise, these
results did not take into account the relative expression levels of
IL-10-related cytokines, their receptors, or their distribution
through psoriatic skin. Furthermore, the expression of
cytokine-binding factors such as IL-22BP which are able to
antagonize cytokine activity, has to be considered.
Currently available treatments, such as topical therapy
(corticosteroids, vitamin D analogues), phototherapy or systemic
therapy (cyclosporine, methotrexate) [120] are now joined by new
drugs focusing on T cell activation and Th1/Th2 balance. Indeed,
the interaction between T cells and antigen-presenting cells
can be inhibited using anti-CD4 monoclonal antibodies or fusion
proteins such as LFA-3/CD58-Ig (alefacept) and CTLA-4/CD152-Ig
[121-124]. The neutralization of Th1 cytokine activities, as for
TNF-α [125, 126] or immune deviation with Th2 cytokines like IL-4,
IL-10 and IL-11 [109, 113, 127, 128] are also promising strategies
of treatment.
Taken together, these data suggest that the cytokines of the
IL-10 family could play a central role in the induction and
maintenance of psoriasis, and open the way to new therapeutic
strategies focusing on more specific targets, i.e. keratinocytes,
rather than a systemic inhibition of cytokine production by T
lymphocytes ( (figure 3) ). The
blockade of these IL-10-related cytokines or their receptors, as
well as others pro-inflammatory cytokines associated with
psoriasis, could be a new approach for psoriasis treatment.
Acknowledgments
We thank Dr. Bruce Koppelman for his careful review of the
manuscript. Katia Boniface is supported by the Conseil Régional de
la Région Poitou-Charentes. This study was supported by grants from
a clinical research program (PHRC) from Poitiers University
Hospital.
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