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1.
J Mol Med (Berl) ; 94(4): 391-400, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26612594

ABSTRACT

UNLABELLED: Psoriasis is considered as a model for chronic immune-mediated disorders. Th17-cells are pivotal players in those diseases. Recently, we demonstrated that Th17-cells produce interleukin (IL)-29 and that IL-29 is highly present in psoriatic lesions. Whether IL-29, with its action on epithelial cells and melanocytes, contributes to psoriasis pathogenesis, was unknown so far. Analysis of IL-29-treated human keratinocytes revealed induction of the chemokines CXCL10, CXCL11, and, to a much lesser extent, CXCL9. Unlike these CXCR3A ligands, known to attract Th1-, CD8(+), NK-, and Th1/Th17 transient cells, no influence was found on chemokines attracting other immune cell populations or on molecules modulating the CXCR3A/CXCR3A ligand interaction. CXCR3A ligand expression was also induced by IL-29 in melanocytes and in epidermis models and explanted skin. Regarding other psoriasis-relevant cytokines, interferon-γ and, less potently, tumor necrosis factor-α and IL-1ß shared and strengthened IL-29's capacity. Murine IL-29 counterpart injected into mouse skin provoked local CXCL10 and CXCL11 expression, T-cell infiltration, and, in consequence, skin swelling. The elevated IL-29 expression in psoriatic lesions was associated with upregulation of CXCR3A ligands compared to non-lesional skin of these patients and to the skin of healthy donors and atopic dermatitis patients, which lack IL-29 production. Importantly, neutralization of IL-29 reduced CXCR3A ligand levels in explant cultures of psoriatic lesions. Finally, elevated blood CXCL11 levels were found in psoriasis that might be useful for monitoring lesional activity of the IL-29 axis. In summary, the Th17-cytokine IL-29 induces specific chemokines and, in consequence, provokes skin infiltration of potentially pathogenic T-cells. KEY MESSAGES: IL-29 selectively induces CXCR3A-binding chemokines (CXCL9, CXCL10, CXCL11) in skin cells. Murine IL-29 counterpart induces skin T-cell infiltration and inflammation in mice. CXCR3A ligands are IL-29-dependently increased in lesional skin of psoriasis patients. CXCR3A ligand levels in psoriatic skin correlate with epidermal T-cell numbers. Increased blood CXCL11 levels in psoriasis may be a biomarker for local IL-29 action.


Subject(s)
Epithelium/immunology , Epithelium/metabolism , Interleukins/metabolism , Receptors, CXCR3/biosynthesis , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Adult , Aged , Animals , Case-Control Studies , Chemokines/metabolism , Chemotaxis , Gene Expression , Humans , Interferons , Interleukins/genetics , Keratinocytes/metabolism , Ligands , Male , Mice , Middle Aged , Psoriasis/immunology , Psoriasis/metabolism , Psoriasis/pathology , Skin/immunology , Skin/metabolism , Skin/pathology , Young Adult
2.
J Invest Dermatol ; 134(11): 2757-2767, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25046339

ABSTRACT

Psoriasis is a common chronic inflammatory disease with characteristic skin alterations and functions as a model of immune-mediated disorders. Cytokines have a key role in psoriasis pathogenesis. Here, we demonstrated that out of 30 individually quantified cytokines, IL-19 showed the strongest differential expression between psoriatic lesions and healthy skin. Cutaneous IL-19 overproduction was reflected by elevated IL-19 blood levels that correlated with psoriasis severity. Accordingly, anti-psoriatic therapies substantially reduced both cutaneous and systemic IL-19 levels. IL-19 production was induced in keratinocytes by IL-17A and was further amplified by tumor necrosis factor-α and IL-22. Among skin cells, keratinocytes were found to be important targets of IL-19. IL-19 alone, however, regulated only a few keratinocyte functions. While increasing the production of S100A7/8/9 and, to a moderate extent, also IL-1ß, IL-20, chemokine C-X-C motif ligand 8, and matrix metalloproteinase 1, IL-19 had no clear influence on the differentiation, proliferation, or migration of these cells. Importantly, IL-19 amplified many IL-17A effects on keratinocytes, including the induction of ß-defensins, IL-19, IL-23p19, and T helper type 17-cell- and neutrophil-attracting chemokines. In summary, IL-19 as a component of the IL-23/IL-17 axis strengthens the IL-17A action and might be a biomarker for the activity of this axis in chronic inflammatory disorders.


Subject(s)
Gene Expression Regulation , Interleukin-17/metabolism , Interleukin-23/metabolism , Interleukins/metabolism , Psoriasis/metabolism , Animals , Cytokines/metabolism , Humans , Inflammation , Keratinocytes/cytology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Skin/immunology , Skin/metabolism , Tumor Necrosis Factor-alpha/metabolism
3.
Sci Transl Med ; 5(204): 204ra129, 2013 Sep 25.
Article in English | MEDLINE | ID: mdl-24068736

ABSTRACT

Psoriasis and atopic dermatitis (AD) are the most common chronic inflammatory skin diseases. Although both patient groups show strongly impaired skin barrier function, only AD patients frequently suffer from cutaneous viral infections. The mechanisms underlying the distinct susceptibilities to these pathogenetic and often life-threatening infections are unknown. We show that antiviral proteins (AVPs) such as MX1, BST2, ISG15, and OAS2 were strongly elevated in psoriatic compared to AD lesions and healthy skin. Of 30 individually quantified cytokines in psoriatic lesions, interleukin-29 (IL-29) was the only mediator whose expression correlated with the AVP levels. IL-29 was absent in AD lesions, and neutralization of IL-29 in psoriatic skin reduced AVP expression. Accordingly, IL-29 raised AVP levels in isolated keratinocytes, epidermis models, and human skin explants, but did not influence antibacterial protein production. AVP induction correlated with increased antiviral defense of IL-29-treated keratinocytes. Furthermore, IL-29 elevated the expression of signaling elements, resulting in increased sensitivity of keratinocytes toward its own action. We identified T helper 17 (T(H)17) cells as IL-29 producers and demonstrated their ability to increase the antiviral competence of keratinocytes in an IL-29-dependent manner. Transforming growth factor-ß and the activity of RORγt/RORα were most critical for the development of IL-29-producing T(H)17 cells. IL-29 secretion by these cells was dependent on NFAT and c-Jun N-terminal kinase and was inhibited by IL-4. These data suggest that T(H)17 cell-derived IL-29, which is absent in AD, mediates the robust antiviral state on psoriatic skin, and demonstrate a new function of T(H)17 cells.


Subject(s)
Interleukins/immunology , Psoriasis/immunology , Psoriasis/virology , Skin/immunology , Skin/virology , Th17 Cells/immunology , Adult , Dermatitis, Atopic/immunology , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/pathology , Dermatitis, Atopic/virology , Herpesvirus 1, Human , Humans , Interferon-gamma/metabolism , Interferons , Interleukins/biosynthesis , Keratinocytes/immunology , Keratinocytes/pathology , Keratinocytes/virology , Signal Transduction/immunology , Th17 Cells/metabolism , Transforming Growth Factor beta/metabolism
4.
Am J Respir Crit Care Med ; 183(9): 1153-63, 2011 May 01.
Article in English | MEDLINE | ID: mdl-21297073

ABSTRACT

RATIONALE: IL-22 has both proinflammatory and antiinflammatory properties. Its role in allergic lung inflammation has not been explored. OBJECTIVES: To investigate the expression and roles of IL-22 in the onset and resolution of experimental allergic asthma and its cross-talk with IL-17A. METHODS: IL-22 expression was assessed in patient samples and in the lung of mice immunized and challenged with ovalbumin. IL-22 functions in allergic airway inflammation were evaluated using mice deficient in IL-22 or anti-IL-22 neutralizing antibodies. Moreover, the effects of recombinant IL-22 and IL-17A neutralizing antibodies were investigated. MEASUREMENTS AND MAIN RESULTS: Increased pulmonary IL-22 expression is found in the serum of patients with asthma and mice immunized and challenged with ovalbumin. Allergic lung inflammation is IL-22 dependent because eosinophil recruitment, Th2 cytokine including IL-13 and IL-33, chemokine production, airway hyperreactivity, and mucus production are drastically reduced in mice deficient in IL-22 or by IL-22 antibody neutralization during immunization of wild-type mice. By contrast, IL-22 neutralization during antigen challenge enhanced allergic lung inflammation with increased Th2 cytokines. Consistent with this, recombinant IL-22 given with allergen challenge protects mice from lung inflammation. Finally, IL-22 may regulate the expression and proinflammatory properties of IL-17A in allergic lung inflammation. CONCLUSIONS: IL-22 is required for the onset of allergic asthma, but functions as a negative regulator of established allergic inflammation. Our study reveals that IL-22 contributes to the proinflammatory properties of IL-17A in experimental allergic asthma.


Subject(s)
Asthma/immunology , Interleukin-17/immunology , Interleukins/immunology , Animals , Asthma/blood , Chemokines/immunology , Cytokines/immunology , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Eosinophils/immunology , Flow Cytometry , Humans , Interleukins/blood , Mice , Mice, Knockout , Th2 Cells/immunology , Interleukin-22
5.
J Immunol ; 186(2): 1228-39, 2011 Jan 15.
Article in English | MEDLINE | ID: mdl-21148041

ABSTRACT

Overexpression of the T cell cytokine IL-22 is linked to the development of some chronic diseases, but little is known about IL-22 deficiency in humans. As demonstrated in this study, acne inversa (AI; also designated as Hidradenitis suppurativa) lesions show a relative deficiency of IL-22 and IL-20, but not of IL-17A, IL-26, IFN-γ, IL-24, or IL-1ß. Moreover, AI lesions had reduced expression of membranous IL-22 and IL-20 receptors and increased expression of the natural IL-22 inhibitor, IL-22 binding protein. AI is a chronic inflammatory skin disease with prevalence up to 4% of the population and in which cutaneous bacterial persistence represents an important pathogenetic factor. Accordingly, we also found a relative deficiency of antimicrobial proteins (AMPs) in AI lesions and a positive correlation between lesional IL-22 and IL-20 versus AMP levels. IL-22, like its tissue cell downstream mediator IL-20, upregulated AMPs in reconstituted human epidermis and was critical for increased AMP levels under inflammatory conditions. The relative IL-22 deficiency in AI was not linked to lesional T cell numbers or Th22/Th1/Th17 subset markers and -inducing cytokines. However, IL-10 was highly expressed in AI lesions and correlated negatively with IL-22 expression. Moreover, IL-10 inhibited IL-22 but not IL-17 production in vitro. The IL-10 overexpression, in turn, was not associated with an elevated presence of regulatory T cells but with the enhanced presence of an IL-10-inducing cytokine. We conclude that IL-22 deficiency may contribute to the pathogenesis of certain chronic disorders as postulated in this paper for AI.


Subject(s)
Hidradenitis Suppurativa/immunology , Hidradenitis Suppurativa/pathology , Inflammation Mediators/physiology , Interleukins/deficiency , Adolescent , Adult , Aged , Animals , Antimicrobial Cationic Peptides/deficiency , Antimicrobial Cationic Peptides/physiology , Cells, Cultured , Chronic Disease , Cytokines/biosynthesis , Cytokines/deficiency , Female , Hidradenitis Suppurativa/metabolism , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Inflammation Mediators/metabolism , Interleukins/genetics , Interleukins/physiology , Male , Mice , Mice, Inbred BALB C , Middle Aged , Up-Regulation/immunology , Young Adult , Interleukin-22
6.
Cytokine Growth Factor Rev ; 21(5): 331-44, 2010 Oct.
Article in English | MEDLINE | ID: mdl-21115385

ABSTRACT

Interleukin (IL)-10 is the most important cytokine with anti-inflammatory properties besides TGF-ß and IL-35. It is produced by activated immune cells, in particular monocytes/macrophages and T cell subsets including Tr1, Treg, and Th1 cells. IL-10 acts through a transmembrane receptor complex, which is composed of IL-10R1 and IL-10R2, and regulates the functions of many different immune cells. In monocytes/macrophages, IL-10 diminishes the production of inflammatory mediators and inhibits antigen presentation, although it enhances their uptake of antigens. Additionally, IL-10 plays an important role in the biology of B cells and T cells. The special physiological relevance of this cytokine lies in the prevention and limitation of over-whelming specific and unspecific immune reactions and, in consequence, of tissue damage. At the same time, IL-10 strengthens the "scavenger"-function and contributes to induced tolerance. This review provides an overview about the cellular sources, molecular mechanisms, effects, and biological role of IL-10.


Subject(s)
B-Lymphocytes/immunology , Interleukin-10/immunology , Macrophages/immunology , Monocytes/immunology , T-Lymphocyte Subsets/immunology , Animals , Humans
7.
Cytokine Growth Factor Rev ; 21(5): 365-79, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20870448

ABSTRACT

Interleukin (IL)-22 is a member of the IL-10 cytokine family that is produced by special immune cell populations, including Th22, Th1, and Th17 cells, classical and non-classical (NK-22) NK cells, NKT cells, and lymphoid tissue inducer cells. This cytokine does not influence cells of the hematopoietic lineage. Instead, its target cells are certain tissue cells from the skin, liver and kidney, and from organs of the respiratory and gastrointestinal systems. The main biological role of IL-22 includes the increase of innate immunity, protection from damage, and enhancement of regeneration. IL-22 can play either a protective or a pathogenic role in chronic inflammatory diseases depending on the nature of the affected tissue and the local cytokine milieu. This review highlights the primary effects of IL-22 on its target cells, its role in the defense against infections, in tumorigenesis, in inflammatory diseases and allergy as well as the potential of the therapeutic modulation of IL-22 action.


Subject(s)
Interleukins/immunology , Killer Cells, Natural/immunology , Natural Killer T-Cells/immunology , T-Lymphocyte Subsets/immunology , Animals , Humans , Immunity, Innate , Interleukin-22
8.
Semin Immunopathol ; 32(1): 17-31, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20127093

ABSTRACT

Interleukin (IL)-22 is a member of the IL-10 family of cytokines and represents an important effector molecule of activated Th22, Th1, and Th17 cells, as well as Tc-cell subsets, gammadelta T cells, natural killer (NK), and NKT cells. IL-22 mediates its effects via a heterodimeric transmembrane receptor complex consisting of IL-22R1 and IL-10R2 and subsequent Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathways including Jak1, Tyk2, and STAT3. Whereas in some aspects, IL-22 acts synergistically with tumor necrosis factor-alpha, IL-1beta, or IL-17, most functions of IL-22 are unique. Importantly, IL-22 does not serve the communication between immune cells. It mainly acts on epithelial cells and hepatocytes, where it favors the antimicrobial defense, regeneration, and protection against damage and induces acute phase reactants and some chemokines. This chapter illuminates in detail the properties of IL-22 with respect to its gene, protein structure, cellular sources, receptors, target cells, biological effects, and, finally, its role in chronic inflammatory diseases, tumors, and infection.


Subject(s)
Interleukins/physiology , Receptors, Interleukin/physiology , Animals , Humans , Signal Transduction/immunology , T-Lymphocyte Subsets/physiology , T-Lymphocytes, Helper-Inducer/physiology , Interleukin-22
9.
Eur J Immunol ; 39(12): 3570-81, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19830738

ABSTRACT

Psoriasis is a common chronic skin disease. Recent studies demonstrated that IL-20 and IL-22, cytokines produced by keratinocytes and T cells, respectively, both inhibit keratinocyte terminal differentiation and induce psoriasis-like epidermis alterations. Here, we investigated the relationship between these mediators. Although IL-20 was not able to regulate IL-22 production, IL-22 induced IL-20 mRNA and protein in human keratinocytes. However, IL-22 had only a minimal effect, if any, on IL-19 and IL-26. Cutaneous IL-20 was also elevated in mice following IL-22 application. Accordingly, some of IL-22's effects on differentiation-regulating genes were partially mediated by an endogenous, secreted protein and attenuated by anti-IL-20 Ab. Like IL-22, IL-17A and TNF-alpha induced IL-20 in keratinocytes, whereas IFN-gamma and IL-20 itself did not. Furthermore, IL-17A and TNF-alpha individually strengthened the IL-22-induced IL-20 production. In lesional skin of psoriasis patients, highly elevated IL-20 levels strongly correlated with IL-22, and to a lesser extent, with IL-17A and TNF-alpha. As previously shown for IL-22, IL-20 blood levels correlated with the disease severity, although with a lower significance. This study demonstrates that a T-cell mediator induces a tissue cell mediator with similar effects to its own and therefore suggests the existence of a novel type of pathogenetic cascade.


Subject(s)
Interleukins/metabolism , Keratinocytes/metabolism , Animals , Cells, Cultured , Enzyme-Linked Immunosorbent Assay , Humans , Immunohistochemistry , Interleukin-17/metabolism , Interleukins/genetics , Interleukins/pharmacology , Keratinocytes/cytology , Keratinocytes/drug effects , Male , Mice , Mice, Inbred BALB C , Psoriasis/blood , Psoriasis/immunology , Psoriasis/pathology , RNA Stability/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Severity of Illness Index , Skin/immunology , Skin/metabolism , Skin/pathology , T-Lymphocytes, Helper-Inducer/metabolism , Tumor Necrosis Factor-alpha/metabolism , Interleukin-22
10.
J Mol Med (Berl) ; 87(5): 523-36, 2009 May.
Article in English | MEDLINE | ID: mdl-19330474

ABSTRACT

Psoriasis is a common chronic skin disease with a largely unknown pathogenesis. We demonstrate here that transgenic over-expression of interleukin (IL)-22 in mice resulted in neonatal mortality and psoriasis-like skin alterations including acanthosis and hypogranularity. This cutaneous phenotype may be caused by the direct influence of IL-22 on keratinocytes, since this cytokine did not affect skin fibroblasts, endothelial cells, melanocytes, or adipocytes. The comparison of cytokines with hypothesized roles in psoriasis pathogenesis determined that neither interferon (IFN)-gamma nor IL-17, but only IL-22 and, with lower potency, IL-20 caused psoriasis-like morphological changes in a three-dimensional human epidermis model. These changes were associated with inhibited keratinocyte terminal differentiation and with STAT3 upregulation. The IL-22 effect on differentiation-regulating genes was STAT3-dependent. In contrast to IL-22 and IL-20, IFN-gamma and IL-17 strongly induced T-cell and neutrophilic granulocyte-attracting chemokines, respectively. Tumor necrosis factor-alpha potently induced diverse chemokines and additionally enhanced the expression of IL-22 receptor pathway elements and amplified some IL-22 effects. This study suggests that different cytokines are players in the psoriasis pathogenesis although only the IL-10 family members IL-22 and IL-20 directly cause the characteristic epidermal alterations.


Subject(s)
Epidermis/drug effects , Interferon-gamma/pharmacology , Interleukin-17/pharmacology , Interleukins/pharmacology , Animals , Blotting, Western , Cell Differentiation/drug effects , Cells, Cultured , Chemokines/genetics , Chemokines/metabolism , Drug Synergism , Enzyme-Linked Immunosorbent Assay , Epidermis/metabolism , Epidermis/pathology , Fibroblasts/drug effects , Fibroblasts/metabolism , Fibroblasts/pathology , Humans , Immunohistochemistry , Interleukins/genetics , Interleukins/metabolism , Keratinocytes/drug effects , Keratinocytes/metabolism , Keratinocytes/pathology , Mice , Mice, Inbred Strains , Mice, Transgenic , Psoriasis/genetics , Psoriasis/metabolism , Psoriasis/pathology , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Interleukin-22
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