Wolfram Sterry

IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes : a potential role in psoriasis

IL‐22 is an IFN–IL‐10 cytokine family member, which is produced by activated Th1 and NK cells and acts primarily on epithelial cells. Here we demonstrate that IL‐22, in contrast to its relative IFN‐γ, regulates the expression of only a few genes in keratinocytes. This is due to varied signal transduction. Gene expressions regulated by IL‐22 should enhance antimicrobial defense [psoriasin (S100A7), calgranulin A (S100A8), calgranulin B (S100A9)], inhibit cellular differentiation (e.g., profilaggrin, keratins 1 and 10, kallikrein 7), and increase cellular mobility [e.g., matrix metalloproteinease 1 (MMP1, collagenase 1), MMP3 (stromelysin 1), desmocollin 1]. In contrast, IFN‐γ favored the expression of MHC pathway molecules, adhesion molecules, cytokines, chemokines, and their receptors. The IL‐22 effects were transcriptional and either independent of protein synthesis and secretion, or mediated by a secreted protein. Inflammatory conditions, but not keratinocyte differentiation, amplified the IL‐22 effects. IL‐22 application in mice enhanced cutaneous S100A9 and MMP1 expression. High IL‐22 levels in psoriatic skin were associated with strongly up‐regulated cutaneous S100A7, S100A8, S100A9, and MMP1 expression. Psoriatic patients showed strongly elevated IL‐22 plasma levels, which correlated with the disease severity. Expression of IL‐22 and IL‐22‐regulated genes was reduced by anti‐psoriatic therapy. In summary, despite similarities, IFN‐γ primarily amplifies inflammation, while IL‐22 may be important in the innate immunity and reorganization of epithelia.

Immunopathogenesis of psoriasis

Abstract:  Psoriasis is a chronic skin disease that affects about 1.5% of the Caucasian population and is characterized by typical macroscopic and microscopic skin alterations. Psoriatic lesions are sharply demarcated, red and slightly raised lesions with silver‐whitish scales. The microscopic alterations of psoriatic plaques include an infiltration of immune cells in the dermis and epidermis, a dilatation and an increase in the number of blood vessels in the upper dermis, and a massively thickened epidermis with atypical keratinocyte differentiation. It is considered a fact that the immune system plays an important role in the pathogenesis of psoriasis. Since the early 1990s, it has been assumed that T1 cells play the dominant role in the initiation and maintenance of psoriasis. However, the profound success of anti‐tumor necrosis factor‐α therapy, when compared with T‐cell depletion therapies, should provoke us to critically re‐evaluate the current hypothesis for psoriasis pathogenesis. Recently made discoveries regarding other T‐cell populations such as Th17 and regulatory T cells, dendritic cells, macrophages, the keratinocyte signal transduction and novel cytokines including interleukin (IL)‐22, IL‐23 and IL‐20, let us postulate that the pathogenesis of psoriasis consists of distinct subsequent stages, in each of them different cell types playing a dominant role. Our model helps to explain the varied effectiveness of the currently tested immune modulating therapies and may enable the prediction of the success of future therapies.

IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-γ are not

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)-γ 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-γ and IL-17 strongly induced T-cell and neutrophilic granulocyte-attracting chemokines, respectively. Tumor necrosis factor-α 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.

Porcine ear skin: an in vitro model for human skin

Background/purpose: Porcine ear skin is used in studies of percutaneous penetration as a substitute for human skin. The structure of this tissue, including hair follicles, was studied qualitatively and quantitatively in comparison with human skin.

Cutaneous side-effects in patients with rheumatic diseases during application of tumour necrosis factor-α antagonists

Background  Patients with rheumatic diseases receiving antitumour necrosis factor (TNF)‐α‐based treatment may develop cutaneous reactions.

IL-22 Induces Lipopolysaccharide-Binding Protein in Hepatocytes: A Potential Systemic Role of IL-22 in Crohn’s Disease

Crohn′s disease (CD) is a common, chronic, inflammatory bowel disease characterized by intestinal infiltration of activated immune cells and distortion of the intestinal architecture. In this study, we demonstrate that IL-22, a cytokine that is mainly produced by activated Th1 and Th17 cells, was present in high quantities in the blood of CD patients in contrast to IFN-γ and IL-17. In a mouse colitis model, IL-22 mRNA expression was elevated predominantly in the inflamed intestine but also in the mesenteric lymph nodes. IL-22BP, the soluble receptor for IL-22, demonstrated an affinity to IL-22 that was at least 4-fold higher than its membrane-bound receptor, and its strong constitutive expression in the intestine and lymph nodes was decreased in the inflamed intestine. To investigate the possible role of systemic IL-22 in CD, we then administered IL-22 to healthy mice and found an up-regulation of LPS-binding protein (LBP) blood levels reaching concentrations known to neutralize LPS. This systemic up-regulation was associated with increased hepatic but not renal or pulmonary LBP mRNA levels. IL-22 also enhanced the secretion of LBP in human primary hepatocytes and HepG2 hepatoma cells in vitro. This increase was mainly transcriptionally regulated and synergistic with that of other LBP inducers. Finally, elevated LBP levels were detected in CD patients and the mouse colitis model. These data suggest that systemic IL-22 may contribute to the prevention of systemic inflammation provoked by LPS present in the blood of CD patients through its induction of hepatic LBP.

Prevention of non-melanoma skin cancer in organ transplant patients by regular use of a sunscreen: a 24 months, prospective, case-control study

Background  Skin cancers represent a major challenge within the ever growing group of long time surviving organ transplant recipients (OTR) world wide. Especially UV‐induced non‐melanoma skin cancers (NMSC) like invasive squamous cell carcinomas (SCC) and actinic keratoses (AK), and basal cell carcinoma (BCC), outnumber every other form of cancer in organ transplant recipients. Despite encouraging reports of protective effects of broad‐spectrum sunscreens in immunocompetent patients, evidence for the prevention of NMSC in immunocompromised patients is still missing.

Actinic keratosis is an early in situ squamous cell carcinoma: A proposal for reclassification

Summary The term actinic keratosis (AK) describes a sun‐induced, clinical erythematous lesion covered with scale, but does not provide an understanding of the biology or histopathology of the lesion. Cousequeutly, several classification systems for AK have been suggested, but as yet no cousensus has been reached. These systems strive to correlate the pathological and clinical features to better provide physcians with the most accurate information to enable correct decisions to be made regarding treatments, Prognosis and metastatic potential. AK is a clinical description that has a histological diagnosis consistent with squamous cell carcinoma (SCC) in situ. We recommend an AK classification system that describes these lesions as squamous cell carcinomas (SCCs), using the terminology ‘early in situ SCC Type AK I’, ‘early in situ SCC type AK II’ and ‘in situ SCC Type AK III’, there by giving clinicians better guidance for diagnosis and specific treatment recommendations.

Biological therapies in the systemic management of psoriasis: International Consensus Conference

Psoriasis is a chronic, immune‐mediated disorder that usually requires long‐term treatment for control. Approximately 25% of patients have moderate to severe disease and require phototherapy, systemic therapy or both. Despite the availability of numerous therapeutic options, the long‐term management of psoriasis can be complicated by treatment‐related limitations. With advances in molecular research and technology, several biological therapies are in various stages of development and approval for psoriasis. Biological therapies are designed to modulate key steps in the pathogenesis of psoriasis. Collectively, biologicals have been evaluated in thousands of patients with psoriasis and have demonstrated significant benefit with favourable safety and tolerability profiles. The limitations of current psoriasis therapies, the value of biological therapies for psoriasis, and guidance regarding the incorporation of biological therapies into clinical practice are discussed.

S3 – Guidelines on the treatment of psoriasis vulgaris (English version). Update

Psoriasis vulgaris is a common and often chronic inflammatory skin disease. The incidence of psoriasis in Western industrialized countries ranges from 1.5% to 2%. Patients afflicted with severe psoriasis vulgaris may experience a significant reduction in quality of life. Despite the large variety of treatment options available, surveys have shown that patients still do not received optimal treatments. To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologi sche Gesellschaft (DDG) and the Berufsverband Deutscher Dermatologen (BVDD) have initiated a project to develop evidence‐based guidelines for the management of psoriasis. They were first published in 2006 and updated in 2011. The Guidelines focus on induction therapy in cases of mild, moderate and severe plaque‐type psoriasis in adults including systemic therapy, UV therapy and topical therapies.