Home > Journals > Biology and research > European Cytokine Network > Full text
      Advanced search    Shopping cart    French version 
Latest books
All journals
Biology and research
European Cytokine Network
- Current issue
- Archives
- Subscribe
- Order an issue
- More information
Public health
Agronomy and biotech.
My account
Forgotten password?
Online account   activation
Licences IP
- Instructions for use
- Estimate request form
- Licence agreement
Order an issue
Pay-per-view articles
How can I publish?
Help for advertisers
Foreign rights
Book sales agents


Texte intégral de l'article
  Printable version
  Version PDF

Cytokine network in psoriasis revisited

European Cytokine Network. Volume 22, Number 4, 160-8, December 2011, Review article

DOI : 10.1684/ecn.2011.0294


Author(s) : Anna Michalak-Stoma, Aldona Pietrzak, Jacek C. Szepietowski, Anna Zalewska-Janowska, Tomasz Paszkowski, Grażyna Chodorowska, Department of Dermatology, Venereology and Paediatric Dermatology, Medical University of Lublin, ul. Radziwiłłowska 13, 20-080 Lublin, Poland, Department of Dermatology, Venereology and Allergology, Medical University of Wrocław, ul. Chałubińskiego 1, 50-368 Wrocław, Poland, Psychodermathology Department, Chair of Clinical Immunology and Microbiology, Medical University of Łódź, ul. Pomorska 251, 92-213 Łódź, Poland, III Department of Gynecology, Medical University of Lublin, ul. Jaczewskiego 8, 20-094 Lublin, Poland.

Summary : Psoriasis is a chronic genetically determined, erythemato-squamous disease associated with many comorbidities. Evidence from clinical studies and experimental models support the concept that psoriasis is a T cell-mediated inflammatory skin disease and T helper (Th) cells – Th1, Th17 and Th22 – play an important role in the pathogenesis. Th1 cytokines IFNγ, IL-2, as well as Th17 cytokines IL-17A, IL-17F, IL-22, IL-26, and TNFα (Th1 and Th17 cytokine) are increased in serum and lesional skin. IL-22 produced by Th17 and new subset of T helper cells, Th22, is also increased within psoriatic lesions and in the serum. Other recently recognized cytokines of significant importance in psoriasis are IL-23, IL-20 and IL-15. The IL-23/Th17 pathway plays a dominant role in psoriasis pathogenesis. Currently due to enormous methodological progress, more and more clinical and histopathological psoriatic features could be explained by particular cytokine imbalance, which still is one of the most fascinating dermatological research fields stimulating new and new generations of researchers.

Keywords : psoriasis, interleukin, cytokine, Th1, Th17, Th2




Auteur(s) : Anna Michalak-Stoma1 annamichalak@wp.pl, Aldona Pietrzak1, Jacek C. Szepietowski2, Anna Zalewska-Janowska3, Tomasz Paszkowski4, Grażyna Chodorowska1

1 Department of Dermatology, Venereology and Paediatric Dermatology, Medical University of Lublin, ul. Radziwiłłowska 13, 20-080 Lublin, Poland

2 Department of Dermatology, Venereology and Allergology, Medical University of Wrocław, ul. Chałubińskiego 1, 50-368 Wrocław, Poland

3 Psychodermathology Department, Chair of Clinical Immunology and Microbiology, Medical University of Łódź, ul. Pomorska 251, 92-213 Łódź, Poland

4 III Department of Gynecology, Medical University of Lublin, ul. Jaczewskiego 8, 20-094 Lublin, Poland

Correspondence: Anna Michalak-Stoma, Department of Dermatology, Venereology and Paediatric Dermatology, Medical University of Lublin, ul. Radziwiłłowska 13, 20-080 Lublin, Poland


Psoriasis is a chronic genetically determined, erythemato-squamous disease affecting approximately 2-3% of the world's population. About 6-20% of psoriatic patients develop a chronic inflammatory arthritis or enthesitis [1]. Comorbidities associated with psoriasis include other inflammatory conditions such as Crohn's disease and an elevated risk of cardiovascular diseases, lymphomas, diabetes, metabolic syndrome, depression and mortality [2-4].

The histological changes observed within lesional skin include acanthosis, hypogranulosis, parakeratosis, marked dilatation of blood vessels in the papillary dermis, and infiltration of monocytes, dendritic cells (DCs) and T cells. Evidence from clinical studies and experimental models support the concept that psoriasis is a T cell-mediated inflammatory skin disease and T helper (Th) cells – Th1, Th17 and Th22 – play an important role in the pathogenesis [4, 5] (figure 1).

Th1 cytokines IFNγ, IL-2, as well as Th17 cytokines IL-17A, IL-17F, IL-22, IL-26, and TNFα (Th1 and Th17 cytokine) are increased in serum and lesional skin [5]. IL-22 produced by Th17 and Th22 is also increased within psoriatic lesions and in the serum [5-8]. Differentiation of naive CD4+ cells into different T cell subsets depends on specific immune conditions (figure 2).

Th1 cells differentiate from naive CD4+ cells in the presence of IL-12, IL-18 and IFNα and γ. Th1 cells have been associated with the development and maintenance of chronic inflammatory diseases, such as psoriasis, inflammatory bowel disease (IBD), multiple sclerosis (MS), and rheumatoid arthritis (RA), through Th1 cytokines have an effect on macrophage, neutrophil and CD8+ cytotoxic T cell activation [9].

Th17 cells require a combination of TGF-β1 and proinflammatory cytokines (IL-1b, IL-6 and/or IL-21) to differentiate. This finding was initially surprising because TGF-β1 is known to induce the development of regulatory T cells with a potent suppressor function [10, 11]. TGF-β1 may be secreted by activated T cells to initiate T cell and fibroblast activation, as well as angiogenesis and neovascularization [12-16]. IL-6 is secreted by macrophages, endothelial cells, and epithelial cells, and augments keratinocyte hyperplasia and invasion of macrophages and T cells [16, 17]. Upregulation of the IL-23 receptor makes Th17 cells responsive to IL-23. Some studies suggested that IL-15, produced by monocytes, macrophages, DCs, and T cells, can also induce Th17 cells [16-19]. IL-15 can appear to induce angiogenesis, immune cell (including Langerhans cells [LCs]) recruitment, and activation of keratinocytes (KCs) [12, 20, 21].

Th22 cells have been recently described as inflammatory CD4+ T cells that produce cytokines such as IL-22, IL-26, and IL-13, of which IL-22 is the most important functional cytokine. Recent studies indicate that IL-6 and TNFα, along with the help of plasmacytoid dendritic cells (pDCs), can promote the Th22 phenotype [7, 22].

Th1 cytokines

Interleukin 2 (IL-2)

IL-2 is produced by T cells upon antigen binding to the T-cell receptor (IL-2R). The IL-2 receptor plays a key role in the antimicrobial response and in discrimination between non-self and self immune response. The IL-2R is present in three different forms: high, intermediate and low-affinity complexes. The high-affinity receptor consists of three subunits: α (CD25, Tac), β (CD122), and γ (CD132). The intermediate and low-affinity receptors consist of the β and γ subunits, and the α subunit, respectively [23, 24]. The high-affinity IL-2R is present on actively proliferating T lymphocytes, recently activated B cells, monocytes and a small population of resting natural killer (NK) cells, although most NK cells express the intermediate affinity receptor isoform [23].

The IL-2/IL-2R interaction stimulates the growth, differentiation and survival of antigen-selected CD8+ T cells via the activation of the expression of specific genes. IL-2 is also necessary during T cell development in the thymus for the maturation of regulatory T cell subset. It stimulates activity and proliferation of NK cells, monocytes, macrophages, steam cells in bone marrow, lymphokine-activated killers (LAK) and tumour infiltrating lymphocytes (TIL), as well as differentiation of B cells (together with IL-15). IL-2 induces production of IFNγ, TNF, IL-6, GM-CSF, IL-2R and IL-2 [25]. IL-2 has a well documented role in induction of pruritus in atopic dermatitis, psoriasis and uraemia [26, 27].

Many drugs used in therapy of psoriasis reduce IL-2 activity by blocking the T cell production of IL-2 (ciclosporin A, tacrolimus, vitamin D3 analogues) and/or by decreasing the expression of IL-2R (ciclosporin A, UVB and PUVA) [28].

Interferon gamma (IFNγ)

IFNγ is the only type II interferon, classified to this group because of its unique amino acid sequence. Receptors for IFNγ are located on the surface of many cells, but its expression differs from cell to cell. The highest expression is observed on T and B cells, NK cells, monocytes, macrophages, fibroblasts, neutrophils, endothelial and smooth muscle cells [23].

IFNγ influences the immune response regulating activation, proliferation and differentiation of T cells, B cells, macrophages, NK cells, fibroblasts and endothelial cells. IFNγ stimulates production of many proinflammatory factors like IL-1, IL-6, IL-8, IL-12, IL-15, TNF, IFNγ-induced protein 10 (IP-10), inducible NO synthase (iNOS), kaspase-1 and gp91phox (NOX2), a subunit of NADPH oxidase [23]. IFNγ has been shown to stimulate DCs to produce IL-1 and IL-23, which are Th17 and Th22 promoting cytokines [29, 30]. Recently a distinct subset of human Th17 cells have also been shown to produce IFNγ [31-33]. IFNγ increases the production of antibodies in response to antigens administered simultaneously with IFNα, expression of MHC class I and II molecules on antigen presenting cells (APCs) as well as expression of ICAM-1 on KCs and endothelium [25, 34].

Literature data on the IFNγ levels in serum and lesional and nonlesional skin in psoriatic patients are controversial. However more authors demonstrated elevated serum IFNγ level in psoriatic patients and correlated it with the clinical severity of psoriasis [31, 35-39]. Uyemura et al. observed strong IFNγ expression not only in psoriatic lesions, but also in the nonlesional skin [40]. Many authors state that IFNγ detected in the psoriatic skin is locally produced and does not originate from the peripheral blood [25]. Barna et al. obtained clones of different T cells from psoriatic lesions, producing different levels of IFNγ and IL-4, suggesting presence of both Th1 and Th2 cells [41].

A significant decrease in expression of IFNγ and biologically active IL-23 (IL-12/IL-23p40+IL-23p19) in the epidermis and dermis of psoriatic lesions was observed after PUVA therapy [42].

Th1/Th17 cytokine: tumor necrosis factor alpha (TNFα)

Biologically active forms of TNFα, both membrane and soluble ones, are homotrimers consisting of 3 identical protein chains of non-convalescent bindings [43, 44]. There are two TNF cell receptors: TNF-RI (also called TNF-R55, TNF-Rβ, p55, CD120a) and TNF-RII (TNF-R75, TNF-Rα, p75, CD120b) presented on all cell types except for erythrocytes. TNF-RI seems to be responsible for the majority of TNF activity. Soluble forms of both TNF receptors, TNF-RI and TNF-RII, are encountered in the blood. By binding TNF, soluble receptors exert an inhibitory or modulatory effect on TNF itself [43, 45].

TNFα is a prominent mediator of psoriatic inflammation and therefore it is a major target of biologic therapeutics. TNFα appears to be a point of convergence for Th1 and Th17 cells. Proteins of TNF superfamily influence the proliferation, activation and differentiation of many cells and even stimulate apoptosis [25, 45, 46]. TNF enhances the synthesis of IL-1, IL-6, GM-CSF, leukemia inhibitory factor (LIF), TGF, B4 leukotriene (LTB4), PGE2 and expression of some adhesion molecules (E-selectin, ICAM-1, VCAM-1) [46-48]. TNFα induces APCs to secrete IL-23 and upregulate the Th17 cell response [49-51].

An elevated level of TNF in the lesional psoriatic skin in comparison to both nonlesional and normal skin was observed [52, 53]. Overexpressed TNF is localised in the epidermis and around blood vessels in the upper dermis [54]; its sources are KCs, epidermal LCs and macrophages in the papillary dermis [54]. The majority of authors observed increased plasma TNF levels in active psoriatic patients [37, 52, 55]. It is worth underlining that plasma TNF levels are significantly lower than the ones found in suction blister fluid, which suggests that this cytokine is produced locally [25]. A positive correlation between serum TNF levels and PASI score was demonstrated [52, 55, 56]. In the normal skin and unaffected skin of psoriatic patients, TNF-RI is expressed on epidermal KCs and on dermal DCs. In lesional psoriasis skin, TNF-RI, and soluble TNF-RI and TNF-RII were detected in the parakeratotic stratum corneum. Moreover, plasma TNF-RI levels in psoriatic patients were significantly increased compared to those in healthy people [25, 57].

A decrease in TNF cytokine levels after successful anti-psoriatic treatment using different methods, including PUVA, UVB plus topical corticosteroids and dithranol, was observed [37, 55, 58]. The treatment with cyclosporin A, acitretin or Goeckerman method did not exert any influence on TNF protein levels [59]. The TNF antagonist treatment of both psoriasis arthropatica and vulgaris is most widely used and thoroughly studied in clinical practice amongst all anti-cytokine therapies for psoriasis [60].

Th17 cytokines

Interleukin 17 (IL-17A)

IL-17 (IL-17A) is a member of a newly identified cytokine family comprising IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F. Very little is known about IL-17B, IL-17C, and IL-17D, which are produced by non-T-cell sources, whereas IL-25 and IL-17F share many features with IL-17A [10, 61]. T cells producing IL-17 are now recognized as a third Th cell subset: Th17 cells [62, 63]. Other IL-17A-producing cells have also been reported, including CD8+ cells [64], γδ-TCR cells [65-67], DCs [68] and NK cells [69, 70]. IL-17F and IL-17A have 50% sequence homology and they can form IL-17A and IL-17F homodimers or IL-17A-IL-17F heterodimers [10].

There are two receptor for IL-17: IL-17 receptor A (IL-17RA) and IL-17RC. IL-17RA and RC interact together for an optimal response. The inhibition of the two receptors is needed to reduce the response to the combination of IL-17 with TNF [63]. IL-17 and IL-17F have a proinflammatory activity inducing the expression of proinflammatory cytokines, colony-stimulating factors, and chemokines from DCs, neutrophils, T cells, monocyte/macrophages, and epithelial cells [10, 71]. Cells selectively producing IL-17 express the chemokine receptors CCR6 and CCR4, whereas cells producing both IL-17 and IFNγ express CCR6 and CXCR3 [72, 73]. Hirota et al. reported that CCR6 was critical for leukocyte migration into inflammed joints in a mouse model RA [74]. IL-17 expression is increased in inflammatory tissues [9, 71]. IL-17A and IL-17F link also specific and non-specific immune response, because they can mobilize, recruit, and activate neutrophils [10, 61]. In keratinocyte experimental systems, IL-17 and IL-22 act together to induce the proliferation and expression of co-stimulatory immune molecules and downstream immune modulators such as neutrophilic and monophilic chemokines, cellular adhesion molecules, and intracellular transcription factors [12].

IL-23/IL-17 pathway is linked to mucosal host defense against extracellular pathogens [75, 76] and to the induction and progression of many inflammatory diseases, including psoriasis [9, 32, 33]. Normally, IL-17A is present in extremely low or undetectable concentrations in human sera but it is increased in serum and tissue in IBD, MS, and RA [10, 71].

Th17 cells and the cytokines produced by these cells are found in increased levels within skin affected by psoriasis [30, 31, 33, 49, 77, 78]. IL-17-producing cells have been isolated from the dermis of psoriatic lesions by flow cytometry [77] and surface phenotypic analysis of these cells showed a predominantly CD161+ phenotype [79]. DCs isolated from psoriatic skin are able to increase the percentage of IL-17A production in allogenic T cells [49]. IL-17A and IL-17F mRNA were observed in psoriatic skin lesion comparing to nonlesional or healthy skin [5, 33, 49, 73, 78]. In psoriasis no statistically significant differences in peripheral levels of IL-17A have been found. IL-17 and IL-22 may act cooperatively in mediating tissue inflammation by upregulation of antimicrobial peptides human β-defensin (hBD-2), S100A7 (psoriasin), S100A8, S100A9 and matrix metalloproteinase 3 (MMP-3) transcripts in primary KCs [9, 80].

Th17/Th22 cytokine: interleukin 22 (IL-22)

IL-22 is a member of the IL-10 cytokines family, and is mainly produced by Th17, Th22 and mucosal NK cells [75, 78, 81]. This subset of NK cells (NK-22 cells) produces IL-22 in response to IL-23 and may inhibit inflammation (through IL-10 production) and provide mucosal protection (via epithelial cell proliferation) [81]. Th22 cells are recently described inflammatory CD4+ T cells that produce IL-22, but do not express IL-17A or IFNγ [29, 82-84]. Th22 cells are also increased within psoriatic lesions [29, 31, 84].

The IL-22 receptor (IL-22R) is part of the cytokine receptor family class 2 and consists of two subunits, IL-22R1 and IL-10R2 [85, 86]. IL-10R2 is expressed on immune cells (T, B, and NK cells), and IL-22R1 in a variety of nonimmune tissues: skin, lung, small intestine, liver, colon, kidney, and pancreas [84]. In KCs the expression of IL-22R1 and IL-10R2 is increased by IFNγ. There is also a soluble, secreted IL-22 receptor called IL-22-binding protein (IL-22BP), which is encoded by a different gene [85, 86]. The affinity of IL-22 to IL-22BP is about four times higher than that of IL-22 to IL-22R1. IL-22 increases the cellular level of STAT3 in the three-dimensional epidermis model which suggests a further positive feedback mechanism for IL-22 effects [85]. Many IL-22 effects can be amplified by TNFα, IL-17, IFNγ or IL-1 [80, 85, 87, 88].

IL-22 promotes antimicrobial defense mechanisms, protects against tissue damage, and reorganizes non-immune tissues, such as epithelia [85]. IL-22 upregulates the expression of acute phase proteins: serum amyloid A (SAA) in the liver and pancreatitis-associated protein 1 (PAP1) in the pancreas [85]. IL-22 increased the expression of the hBD- 2 and hBD-3 in human KCs and MMP1 and MMP3 in the skin and MMP1, MMP3, and MMP10 in the digestive tract [85, 86, 89].

Increased IL-22 mRNA and protein levels have been found both in the skin and blood of psoriatic patients compared to healthy controls [5, 6, 8, 78, 90]. IL-22 mRNA levels were higher in lesional skin than in psoriatic peripheral monocytes [90]. IL-22 levels in plasma correlated with psoriasis severity [78]. The treatment with TNF inhibitor (etanercept) reduced serum levels of IL-17 and IL-22 [91]. IL-22 upregulates keratinocyte proliferation and migration, inhibits keratinocyte differentiation by downregulating a variety of genes as filaggrin and involucrin genes [87, 92], and augments the expression of inflammatory molecules by KCs, which leads to an increase in skin thickness in vitro and in vivo [93-95]. IL-22 can also stimulate epithelial cells to release chemokines, such as IL-8 [5, 80].

Interleukin 26 (IL-26)

IL-26 is a member of the IL-10 cytokine family with almost 25% identity to IL-10. IL-26 is often co-expressed with IL-22 by activated T cells, especially Th17 cells. IL-22 induced IL-20 mRNA and protein in human KCs and had only a minimal effect on IL-19 and IL-26 [96, 97]. IL-26 is a secreted protein, and may be functional either as a monomer or homodimer and signals through a heterodimeric receptor complex composed of the IL-20R1 and IL-10R2 chains. IL-26 receptors are primarly expressed on non-hematopoietic cell types, particularly epithelial cells. Signaling through IL-26 receptor complexes results in the activation of STAT1 and STAT3 with subsequent induction of IL-26-responsive genes. The biological functions of IL-26 is not well known [96].

Other recently recognized cytokines of significant importance in psoriasis

Interleukin 23 (IL-23)

IL-23 together with IL-12 belongs to the IL-12 family and are both structurally related; IL-12 is formed by the p40 and p35 subunits; IL-23 consists of p40 and p19 subunits, and it was discovered in 2000 by Oppmann and co-workers [10, 98]. IL-23 is expressed by activated mouse and human monocytes, macrophages, CD11c+ DCs, T cells, B cells, KCs and endothelial cells [9, 10, 98, 99]. IL-23 production is stimulated by many microorganisms [100] and by the activation of receptors involved in innate immunity, including toll-like receptor-4 (TLR4) [101].

IL-23 exerts its biological activities through the interaction with a heterodimeric receptor complex composed of IL-12Rβ1 and IL-23R [9, 10, 102, 103]. IL-23R is unique to the IL-23 receptor complex and is mainly expressed by T cells, NK cells, and to a lower extent by monocytes and DC populations [9, 102]. The large-scale genomic studies have identified IL-23R as a psoriasis susceptibility gene, whereas no psoriasis association was found for IL-12Rβ1, the signaling receptor for IL-12 [31, 104, 105]. IL-23R expression is enhanced on human memory T cells more than on naive cells [9, 11, 23], suggesting that TCR activation of naive human T cells leads to an upregulation of low levels of IL-23R expression, causing sensitization of the cells to IL-23. Furthermore, IL-23 increases its own receptor expression on activated naive T cells [9, 23]. IL-23 is a key cytokine in bridging the innate and adaptive immune response [106, 107]. Interaction of IL-23-IL23R augments the proliferation of the differentiated Th17 cells characterized by the production of IL-17A and other related proinflammatory cytokines, activates NK cells, and regulates antibody production [10, 16, 108, 109]. In IL-23 knockout mice Th17 cells were not detected, which can suggest a critical role for IL-23 in the development and expansion of that T cell subset [106, 110]. IL-23 also regulates proinflammatory cytokines which are important in cell-mediated immunity against intracellular pathogens [106].

Although both IL-12 and IL-23 are present in psoriasis, studies support that IL-23, rather than IL-12, is crucial in psoriasis pathogenesis. IL-23 is overexpressed in psoriasis lesional skin, as shown for example by increased p40 and p19 mRNA levels, but not always p35 [9, 31, 33, 49, 111-115]. IL-23 is overproduced by dermal DCs [33, 114] and KCs [112] in lesional psoriatic skin, and is able to induce the Th17 cytokines release that act on KCs which produce more IL-23 as well as pro-inflammatory cytokines, chemokines, members of the S100 family and antimicrobial peptides. They exert their influence on sustenance and amplification of the chronic inflammation in psoriasis [116]. In contrast, most recent reports show no increased expression of IL-12 in psoriasis [16, 49, 113, 114]. It was observed that intradermal injection of IL-23 in mice induced a psoriasis-like phenotype including a dramatic increase in erythema, induration, acanthosis and parakeratosis of the skin [9, 113, 117]. Furthermore, IL-23 was shown to mediate epidermal hyperplasia, acanthosis, hyperparakeratosis, and orthohyperkeratosis through TNFα and IL-20R2 [113]. It was shown that clinical improvement in psoriatic patients, who were put on anti-IL-12p40-neutralizing antibodies, was associated with reduced expression of IL-12p40 and IL-23p19 but not of IL-12p35 [9, 118]. Genetic studies revealed that single nucleotide polymorphisms in both the IL12B and IL23R genes, coding for IL-12/23p40 and IL23R subunits, respectively, are associated with higher risk of susceptibility to psoriasis [9, 104, 105, 116], making it very likely that the IL-23/Th17 pathway plays a dominant role in this disease.

Interleukin 20 (IL-20)

IL-20 resembles IL-22 structurally and belongs to the same cytokine family. IL-20 is produced by KCs in the presence of IL-22, TNFα and IL-17 but not IFNγ or IL-20 itself [84, 119]. Stimulated monocytes and DCs are also capable of producing this cytokine [120-122]. There are two different receptor complexes for IL-20: IL-22R1/IL-20R2 and IL-20R1/IL-20R2 [84, 123]. Thus the IL-22R1 chain is a component of both the IL-22 as well as the IL-20 receptor system. The receptors for IL-20 are found exclusively on non-hematopoietic tissue cells [120-122]. Most effects of IL-20 on KCs are primarily mediated by the IL-22R1/IL-20R2 receptor.

Psoriasis patients exhibit increased levels of IL-20 in the lesional skin as well as in the blood [122]. IL-20 blood levels correlate with PASI scores of the patients [119]. IL-20 can play an important role in the later effector phase of psoriasis pathogenesis, in which inhibits terminal differentiation, increases antimicrobial competence and production of chemokines for neutrophils in KCs [119, 124].

Interleukin 15 (IL-15)

IL-15, an IL-2-like cytokine, is a proinflammatory cytokine. IL-15 recruits and activates T cells and other inflammatory cells and can induce TNFα, IFNγ and IL-17 production as a downstream cascade [25, 125, 126]. IL-15 upregulates Th17 response [16, 17, 19, 127]. It has also an antiapoptotic function, and can induce angiogenesis, immune cell recruitment, and activation of KCs [12, 20, 21, 25, 128].

IL-15 is expressed in psoriatic skin lesions and is also present in the synovium of patients with psoriasis arthritis [1, 128-130]. IL-15 has a great influence on pathophysiologic components of psoriatic skin including angiogenesis, neutrophil and macrophage recruitment and activation, activation of cytotoxic T cells, and acanthosis [128, 129, 131-133]. When anti-IL-15 antibodies were injected into immunocompromised mice with xenografted psoriatic skin, resolution of psoriatic lesions with a downregulation of hyperkeratosis, parakeratosis, and inflammatory cell proliferation were observed [134]. Genetic polymorphisms in the IL-15 gene are linked to a genetic susceptibility to psoriasis [135, 136].


A few years ago scientists deeply engaged in dermatological research were quite firmly convinced that psoriasis is a fairly stabilized disease from the therapeutic and pathogenetic point of view, bearing in mind that psoriasis pathogenesis was not fully elucidated, just like nowadays.

Much to all dermatologists surprise, breakthrough research and biologic agents efficacy in psoriasis treatment urged a new wave of intensive work in this subject. Professor Enno Christophers used to say that if someone starts to investigate psoriasis as a resident, will still be full-time occupied with this fascinating condition when preparing oneself for a pension benefit. And this statement still continues to be a very true one.

Currently, due to enormous methodological progress, more and more clinical and histopathological psoriatic features could be explained by particular cytokine imbalance, which is still one of the most fascinating dermatological research fields, stimulating new and new generations of researchers. Let explanation of cytokine network thrive in this disease!


Conflict of interest: none.


1. Hueber AJ, McInnes I.B. Immune regulation in psoriasis and psoriatic arthritis-recent developments. Immunol Lett 2007 ; 114 : 59-65.

2. Prinz J.C. From bench to bedside - translational research in psoriasis. JEADV 2010 ; 24 : 1-4.

3. Gelfand JM, Troxel AB, Lewis JD et al. The risk of mortality in patients with psoriasis: results from a population-based study. Arch Dermatol 2007; 143: 1493-1499.

4. Mak RKH, Hundhausen C, Nestle F.O. Progress in understanding the immunopathogenesis of psoriasis. Actas Dermosifiliogr 2009 ; 100 : 2-13.

5. Kagami S, Rizzo HL, Lee JJ et al. Circulating Th17, Th22, and Th1 Cells Are Increased in Psoriasis. J Invest Dermatol 2010; 130: 1373-1383.

6. Duhen T, Geiger R, Jarrossay D et al. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol 2009; 10: 857-863.

7. Liu Y, Yang B, Zhou M et al. Memory IL-22-producing CD4(+) T cells specific for Candida albicans are present in humans. Eur J Immunol 2009; 39: 1472-1479.

8. Trifari S, Kaplan CD, Tran EH et al. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol 2009; 10: 864-871.

9. Boniface K, Blom B, Liu YJ, de Waal Malefyt R. From interleukin-23 to T-helper 17 cells: human T-helper cell differentiation revisited. Immunol Rev 2008; 226: 132-146.

10. Di Cesare A, Di Meglio P and Nestle FO. The IL-23/Th17 Axis in the Immunopathogenesis of Psoriasis. J Invest Dermatol 2009; 129: 1339-1350.

11. Chen Z, O'Shea JJ. Regulation of IL-17 production in human lymphocytes. Cytokine 2008; 41: 71-78.

12. Asarch A, Barak O, Loo DS, Gottlieb AB. Th17 cells: A new therapeutic target in inflammatory dermatoses. J Dermatolog Treat 2008; 19: 318-326.

13. Baran W, Szepietowski JC, Mazur G, Baran E. TGF-beta(1) gene polymorphism in psoriasis vulgaris. Cytokine 2007; 38: 8-11.

14. Nockowski P, Szepietowski JC, Ziarkiewicz M, Baran E. Serum concentrations of transforming growth factor beta 1 in patients with psoriasis vulgaris. Acta Dermatovenerol Croat 2004; 12: 2-6.

15. McGeachy MJ, Cua DJ. T cells doing it for themselves: TGFbeta regulation of Th1 and Th17 cells. Immunity 2007; 26: 547-549.

16. Asarch A, Barak O, Loo DS, Gottlieb AB. Th17 cells: A new paradigm for cutaneous inflammation. J Dermatolog Treat 2008; 19: 259-266.

17. Grossman RM, Krueger J, Yourish D et al. Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc Natl Acad Sci U S A 1989; 86: 6367-6371.

18. Miranda-Carus ME, Benito-Miguel M, Llamas MA et al. Human T cells constitutively express IL-15 that promotes ex vivo T cell homeostatic proliferation through autocrine/juxtacrine loops. J Immunol 2005; 175: 3656-3662.

19. Tesmer LA, Lundy SK, Sarkar S, Fox DA. Th17 cells in human disease. Immunol Rev 2008; 223: 87-113.

20. McInnes IB, Gracie JA. Interleukin-15: A new cytokine target for the treatment of inflammatory diseases. Curr Opin Pharmacol 2004; 4: 392-397.

21. Villadsen LS, Schuurman J, Beurskens F et al. Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model. J Clin Invest 2003; 112: 1571-1580.

22. Zhang N, Pan HF, Ye DQ. Th22 in inflammatory and autoimmune disease: prospects for therapeutic intervention. Mol Cell Biochem 2011; 353: 41-46.

23. Pietrzak A, Zalewska A, Chodorowska G et al. Genes and structure of selected cytokines involved in pathogenesis of psoriasis. Folia Histochem Cytobiol 2008; 46: 11-21.

24. Minami Y, Kono T, Miyazaki T, Taniguchi T. The IL-2 receptor complex: its structure, function, and target genes. Annu Rev Immunol 1993; 11: 245-267.

25. Pietrzak AT, Zalewska A, Chodorowska G et al. Cytokines and anticytokines in psoriasis. Clin Chim Acta 2008; 394: 7-21.

26. Reich A, Szepietowski JC. Mediators of Pruritus in Psoriasis. Mediators Inflamm 2007; 2007:64727.

27. Nakamura M, Toyoda M, Morohashi M. Pruritogenicmediators in psoriasis vulgaris: comparative evaluation of itch-associated cutaneous factors. Br J Dermatol 2003; 149: 718-730.

28. Franchi C, Cainelli G et al. Association of cyclosporine and 311 nM UVB in the treatment of moderate to severe forms of psoriasis: a new strategic approach. Int J Immunopathol Pharmacol 2004; 17: 401-406.

29. Nograles KE, Davidovici B, Krueger JG. New insights in the Immunologic Basis of Psoriasis. Semin Cutan Med Surg 2010; 29: 3-9.

30. Kryczek I, Bruce AT, Gudjonsson JE, et al. Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis. J Immunol 2008; 181: 4733-4741.

31. Harper EG, Guo CH, Rizzo H et al. Th17 Cytokines Stimulate CCL20 Expression in Keratinocytes In Vitro and In Vivo: Implications for Psoriasis Pathogenesis. J Invest Dermatol 2009; 129: 2175-2183.

32. Annunziato F, Cosmi L, Santarlasci V et al. Phenotypic and functional features of human Th17 cells. J Exp Med 2007; 204: 1849-61.

33. Wilson NJ, Boniface K, Chan JR, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 2007; 8: 950-957.

34. Little MC, Gawkrodger DJ, Mac Neil S. Differentiation of human keratinocytes is associated with a progressive loss of interferon-γ-induced intercellular adhesion molecule 1 expression. Br J Dermatol 1996; 135: 24-31.

35. Szegedi A, Aleksza M, Gonda A et al. Elevated rate of Thelper1 (TH1) lymphocytes and serum IFN-γ levels in psoriatic patients. Immunol Lett 2003; 86: 277-280.

36. Abdel-Hamid MF, Aly DG, Saad NE et al. Serum levels of interleukin-8, tumor necrosis factor-α and γ-interferon in Egyptian psoriatic patients and correlation with disease severity. J Dermatol 2011; 38: 442-446.

37. Chodorowska G. Plasma concentrations of IFN-γ and TNF-α in psoriatic patients before and after local treatment with dithranol ointment. J Eur Acad Dermatol Venereol 1998; 10: 147-151.

38. Austin LM, Ozawa M, Kikuchi T et al. The majority of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol 1999; 113: 752-759.

39. Zhou X, Krueger JG, Kao MC et al. Novel mechanisms of T-cell and dendritic cell activation revealed by profiling of psoriasis on the 63,100-element oligonucleotide array. Physiol Genomics 2003; 13: 69-78.

40. Uyemura K, Yamamura M, Fivenson DF et al. The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. J Invest Dermatol 1993; 101: 701-705.

41. Barna M, Snijdewint FGM, Van der Heijden FL et al. Characterization of lesional psoriatic skin T lymphocyte clones. Acta Derm Venereol Suppl (Stockh) 1994; 186: 9-11.

42. Ravić-Nikolić A, Radosavljević G, Jovanović I et al. Systemic photochemotherapy decreases the expression of IFN-γ, IL-12p40 and IL-23p19 in psoriatic plaques. Eur J Dermatol 2011; 21: 53-57.

43. Goetz FW, Planas JV, MacKenzie S. Tumor necrosis factor. Dev Comp Immunol 2004; 28: 487-495.

44. Schottelius AJG, Moldawer LL, Dinarello CA et al. Biology of tumor necrosis factor-α - implications for psoriasis. Exp Dermatol 2004; 13: 193-222.

45. Ware CF. The TNF superfamily. Cytokine Growth Factor Rev 2003; 14: 181-184.

46. Makhatadze NJ. Tumor necrosis factor locus: genetic organisation and biological implications. Human Immunol 1998; 59: 571-579.

47. Aggarwal BB, Natarajan K. Tumor necrosis factors: developments during the last decade. Eur Cytokine Netw 1996; 7: 93-124.

48. Groves RW, Allen MH, Ross EL et al. Tumor necrosis factor alpha is pro-inflammatory in normal human skin and modulates cutaneous adhesion molecule expression. Br J Dermatol 1995; 132: 345-352.

49. Zaba LC, Cardinale I, Gilleaudeau P et al. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J Exp Med. 2007; 204: 3183-3194.

50. Gottlieb AB, Chamian F, Masud S et al. TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J Immunol 2005; 175: 2721-2729.

51. Iwamoto S, Iwai S, Tsujiyama K et al. TNF-alpha drives human CD14+ monocytes to differentiate into CD70+ dendritic cells evoking Th1 and Th17 responses. J Immunol 2007; 179: 1449-1457.

52. Bonifati C, Carducci M, Cordiali Fei P et al. Correlated increases of tumour necrosis factor-α, interleukin-6 and granulocyte monocyte — colony stimulating factor levels in suction blister fluids and sera of psoriatic patients — relationship with disease severity. Clin Exp Dermatol 1994; 19: 383-387.

53. Ettehadi P, Greaves MW, Wallach D et al. Elevated tumour necrosis factor-alpha (TNF) biological activity in psoriatic skin lesions. Clin Exp Immunol 1994; 96: 146-151.

54. Kristensen M, Chu CQ, Eedy DJ et al. Localization of tumour necrosis factor-alpha (TNF-alpha) and its receptors in normal and psoriatic skin: epidermal cells express the 55-kD but not the 75-kD TNF receptor. Clin Exp Immunol 1993; 94: 354-362.

55. Mussi A, Bonifati C, Carducci M et al. Serum TNF-alpha levels correlate with disease severity and are reduced by effective therapy in plaque-type psoriasis. J Biol Regul Homeost Agents 1997; 11: 115-118.

56. Mizutani H, Ohmoto Y, Mizutani T et al. Role of increased production of monocytes TNF-α, IL-1 β and IL-6 in psoriasis: relation to focal infection, disease activity and responses to treatments. J Dermatol Sci 1997; 14: 145-153.

57. Ettehadi P, Greaves MW, Wallach D et al. Elevated tumour necrosis factor-alpha (TNF) biological activity in psoriatic skin lesions. Clin Exp Immunol 1994; 96: 146-151.

58. Olaniran AK, Baker BS, Paige DG et al. Cytokine expression in psoriatic skin lesions during PUVA therapy. Arch Dermatol Res 1996; 288: 421-425.

59. Tigalonova M, Bjerke JR, Gallati H et al. Serum levels of interferons and TNF-α are not correlated to psoriasis activity and therapy. Acta Derm Venereol 1994; 186: 25-27.

60. Menter A. Recent advances in Psoriasis Therapy and the Work of the International Psoriasis Council. US Derm Review 2006; 1: 23-27.

61. Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 2007; 25: 821-852.

62. Yao Z et al. Human IL-17: a novel cytokine derived from T cells. J Immunol 1995; 155: 5483-5486.

63. Miossec P. IL-17 and Th17 cells in human inflammatory diseases. Microbes and Infection 2009; 11: 625-630.

64. Shin HC, Benbernou N, Esnault S, Guenounou M. Expression of IL-17 in human memory CD45RO+ T lymphocytes and its regulation by protein kinase A pathway. Cytokine 1999; 11: 257-266.

65. Roark CL, Simonian PL, Fontenot AP et al. Gammadelta T cells: an important source of IL-17. Curr Opin Immunol 2008; 20: 353-357.

66. Blauvelt A. T-Helper 17 Cells in Psoriatic Plaques and Additional Genetic Links between IL-23 and Psoriasis. J Invest Dermatol 2008; 128: 1064-1067.

67. Lockhart E, Green AM, Flynn JL. IL-17 production is dominated by gammadelta T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J Immunol 2006; 177: 4662-4669.

68. Coury F, Annels N, Rivollier A et al. Langerhans cell histiocytosis reveals a new IL-17A-dependent pathway of dendritic cell fusion. Nat Med 2008; 4: 81-87.

69. Michel ML, Keller AC, Paget C et al. Identification of an IL-17-producing NK1.1(neg) iNKT cell population involved in airway neutrophilia. J Exp Med 2007; 204: 995-1001.

70. Rachitskaya AV, Hansen AM, Horai R et al. Cutting edge: NKT cells constitutively express IL-23 receptor and RORgammat and rapidly produce IL-17 upon receptor ligation in an IL-6-independent fashion. J Immunol 2008; 180: 5167-5171.

71. Armstrong AW, Voyles SV, Armstrong EJ et al. Rutledge. A tale of two plaques: convergent mechanisms of T-cell-mediated inflammation in psoriasis and atherosclerosis. Exp Dermatol 2011; 20: 544-549.

72. Acosta-Rodriguez EV, Rivino L, Geginat J et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 2007; 8: 639-646.

73. Matsushita S, Higashi T. Human Th17 Cell Clones and Natural Immune Responses. Allergol Int 2008; 57: 135-140.

74. Hirota K, Yoshitomi H, Hashimoto M et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its Animals model. J Exp Med 2007; 204: 2803-2812.

75. Aujla SJ, Dubin PJ, Kolls JK. Th17 cells and mucosal host defense. Semin Immunol 2007; 19: 377-382.

76. Zelante T et al. IL-23 and the Th17 pathway promote inflammation and impair antifungal immune resistance. Eur J Immunol 2007; 37: 2695-2706.

77. Lowes MA, Kikuchi T, Fuentes-Duculan J et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T Cells. J Invest Dermatol 2008; 128: 1207-1211.

78. Wolk K, Witte E, Wallace E et al. IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J Immunol 2006; 36: 1309-1323.

79. Cosmi L, De Palma R, Santarlasci V et al. Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. J Exp Med 2008; 205: 1903-1916.

80. Liang SC et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 2006; 203: 2271-2279.

81. Cella X et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 2009; 457:722-725.

82. Duhen T, Geiger R, Jarrossay D et al. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol 2009; 10: 857-863.

83. Liu Y, Yang B, Zhou M et al. Memory IL-22-producing CD4(+) T cells specific for Candida albicans are present in humans. Eur J Immunol 2009; 39: 1472-1479.

84. Sabat R, Wolk K. Research in practice: IL-22 and IL-20: significance for epithelial homeostasis and psoriasis pathogenesis. J Dtsch Dermatol Ges 2011; doi: 10.1111/j.1610-0387.2011.07611.x.

85. Wolk K, Sabat R. Interleukin-22: a novel T and NK cell derived cytokine that regulates the biology of tissue cells. Cytokine Growth Factor Rev 2006; 17: 367-380.

86. Aujla SJ, Kolls JK. IL-22: A critical mediator in mucosal host defense. J Mol Med 2009; 87: 451-454.

87. Boniface X et al. IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J Immunol 2005; 174: 3695-3702.

88. Zheng X et al. Interleukin 22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 2008; 14: 282-289.

89. Andoh X et al. Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelialmyofibroblasts. Gastroenterol 2005; 129: 969-984.

90. Boniface K, Guignouard E, Pedretti N et al. A role for T cell-derived interleukin 22 in psoriatic skin inflammation. Clin Exp Immunol 2007; 150: 407-415.

91. Caproni M, Antiga E, Melani L et al. Serum levels of IL-17 and IL-22 are reduced by Etanercept, but not by Acitretin, in patients with psoriasis: a randomized controlled trial. J Clin Immunol 2009; 29: 210-214.

92. Gutowska-Owsiak D, Schaupp AL, Salimi M et al. Interleukin-22 downregulates filaggrin expression and affects expression of profilaggrin processing enzymes. Br J Dermatol 2011; 165: 492-498.

93. Tokura Y, Mori T, Hino R. Psoriasis and other Th17-mediated skin diseases. J UOEH 2010; 32: 317-328.

94. Eyerich S, Eyerich K, Pennino D et al. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest 2009; 119: 3573-3585.

95. Tohyama M, Hanakawa Y, Shirakata Y et al. IL-17 and IL-22 mediate IL-20 subfamily cytokine production in cultured keratinocytes via increased IL-22 receptor expression. Eur J Immunol 2009; 39: 2779-2788.

96. Donnelly RP, Sheikh F, Dickensheets H et al. Interleukin-26: An IL-10-related cytokine produced by Th17 cells. Cytokine Growth Factor Rev 2010; 21: 393-401.

97. Ouyang W, Rutz S, Crellin NK et al. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol 2011; 29: 71-109.

98. Oppmann B, Lesley R, Blom B et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000; 13: 715-725.

99. Duvallet E, Semerano L, Assier E et al. Interleukin-23: A key cytokine in inflammatory diseases. Ann Med 2011; doi: 10.3109/07853890.2011.577093.

100. Wendling D. Interleukin 23: a key cytokine in chronic inflammatory disease. Joint Bone Spine 2008; 75: 517-9.

101. Fitch E, Harper E, Skorcheva I, et al. Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines. Curr Rheumatol Rep 2007; 9: 461-467.

102. Parham C et al. A receptor for the hetero- dimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol 2002; 168: 5699-5708.

103. Kastelein RA, Hunter CA, Cua DJ. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol 2007; 25: 221-242.

104. Capon F, Di Meglio P, Szaub J et al. Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. Hum Genet 2007; 122: 201-206.

105. Cargill M, Schrodi SJ, Chang M et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 2007; 80: 273-290.

106. D’Elios MM, Del Prete G, Amedei A. Targeting IL-23 in human diseases. Expert Opin Ther Targets 2010; 14: 759-774.

107. McKenzie BS, Kastelein RA, Cua DJ. Understanding the IL-23-IL-17 immune pathway. Trends Immunol 2006; 27: 17-23.

108. Harrington LE, Hatton RD, Mangan PR et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005; 6: 1123-1132.

109. Langrish CL, Chen Y, Blumenschein WM et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005; 201: 233-240.

110. Dubin PJ, Kolls JK. Th17 cytokines and mucosal immunity. Immunol Rev 2008; 226: 160-171.

111. Tonel G, Conrad C, Laggner U et al. Cutting Edge: A Critical Functional Role for IL-23 in Psoriasis. J Immunol 2010; 185: 5688-569.

112. Piskin G, Sylva-Steenland RM, Bos JD, Teunissen MB. In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol 2006; 176: 1908-1915.

113. Chan JR, Blumenschein W, Murphy E et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med 2006; 203: 2577-2587.

114. Lee E, Trepicchio WL, Oestreicher JL et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med 2004; 199: 125-130.

115. Duffin KC, Woodcock J, Krueger GG. Genetic variations associated with psoriasis and psoriatic arthritis found by genome-wide association. Dermatol Ther 2010; 23: 101-111.

116. Di Meglio P, Nestle FO. The role of IL-23 in the immunopathogenesis of psoriasis. F1000 Biol Rep 2010; 2: 40.

117. Zheng Y et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 2007; 445: 648-651.

118. Toichi E et al. An anti-IL-12p40 antibody down-regulates type 1 cytokines, chemokines, and IL-12/IL-23 in psoriasis. J Immunol 2006; 177: 4917-4926.

119. Wolk K, Witte E, Warszawska K et al. The Th17 cytokine IL-22 induces IL-20 production in keratinocytes: a novel immuno- logical cascade with potential relevance in psoriasis. Eur J Immunol 2009; 39: 3570-3581.

120. Wolk K, Kunz S, Asadullah K, Sabat R. Cutting edge: immune cells as sources and targets of the IL-10 family members? J Immunol 2002; 168: 5397-5402.

121. Wolk K, Witte K, Witte E et al. Maturing dendritic cells are an important source of IL-29 and IL-20 that may cooperatively increase the innate immunity of keratinocytes. J Leukoc Biol 2008; 83: 1181-1193.

122. Kunz S, Wolk K, Witte E et al. Interleukin (IL)-19, IL-20 and IL-24 are produced by and act on keratinocytes and are di- stinct from classical ILs. Exp Dermatol 2006; 15: 991-1004.

123. Sabat R, Wallace E, Endesfelder S, Wolk K. IL-19 and IL-20: two novel cytokines with importance in inflam- matory diseases. Expert Opin Ther Targets 2007; 11: 601-612.

124. Wolk K, Haugen HS, Xu W et al. IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN- gamma are not. J Mol Med 2009; 87: 523-536.

125. Berard M, Brandt K, Bulfone-Paus S, Tough DF. IL-15 promotes the survival of naïve and memory phenotype CD8+ T cells. J Immunol 2003; 170: 5018-5026.

126. Waldmann TA. IL-15 in the life and death of lymphocytes: immunotherapeutic implications. Trends Mol Med 2003; 9: 517-521.

127. Elder JT. IL-15 and psoriasis: another genetic link to Th17? J Invest Dermatol 2007; 127: 2495-2497.

128. Rückert R, Asadullah K, Seifert M et al. Inhibition of keratinocyte apoptosis by IL- 15: a new parameter in the pathogenesis of psoriasis. J Immunol 2000; 165: 2240-2250.

129. Danning CL, Illei GG, Hitchon C et al. Macrophage-derived cytokine and nuclear factor kB p65 expressionn synovial membrane and skin of patients with psoriatic arthritis. Arthritis Rheumat 2000; 43: 1244-1256.

130. Kane D, Gogarty M, O’Leary J et al. Reduction of synovial sublining layer inflammation and proinflamma- tory cytokine expression in psoriatic arthritis treated with methotrexate. Arthritis Rheumat 2004; 50: 3286-3295.

131. Yano S, Komine M, Fujimoto M et al. Interleukin 15 induces the signals of epiderma proliferation through ERK and PI 3-kinase In a human epiderma keratinocyte cell line, HaCaT. Biochem Biophys Res Commun 2003; 301: 841-847.

132. Fehniger TA, Caligiuri MA. Interleukin 15: biology and relevance to human disease. Blood 2001; 97: 14-32.

133. McInnes IB, Gracie JA. Interleukin-15: a new cytokine target for the treatment of inflammatory diseases. Curr Opin Pharmacol 2004; 4: 392-397.

134. Villadsen LS, Schuurman J, Beurskens F et al. Resolution of psoriasis upon blockade of IL- 15 biological activity in a xenograft mouse model. J Clin Invest 2003; 112:1571-1580.

135. Yan KL, Huang W, Zhang XJ et al. Follow-up analysis of PSORS9 in 151 Chinese families confirmed the linkage to 4q31-32 and refined the evidence to the families of early-onset psoriasis. J Invest Dermatol 2007; 127: 312-318.

136. Zhang XJ, Yan KL, Wang ZM et al. Polymorphisms in interleukin-15 gene on chromosome 4q31.2 are associated with psoriasis vulgaris in Chinese population. J Invest Dermatol 2007; 127: 2544-2551.


About us - Contact us - Conditions of use - Secure payment
Latest news - Conferences
Copyright © 2007 John Libbey Eurotext - All rights reserved
[ Legal information - Powered by Dolomède ]