Interleukin 22 (IL-22) is mainly produced by activated Th1 cells. The data presented here indicate that neither resting nor activated immune cells express IL-22 receptor, and IL-22 did not have any effects on these cells in vitro and in vivo. In contrast, cells of the skin and the digestive and respiratory systems represent putative targets of this cytokine. The expression of IL-22 receptor in keratinocytes was upregulated by Interferon-gamma. In these cells, IL-22 activated STAT3 and directly and transcriptionally increased the expression of beta-Defensin 2 and beta-Defensin 3. High levels of IL-22 were associated with strongly upregulated beta-Defensin expression in skin from patients with T cell-mediated dermatoses. Taken together, IL-22 does not serve the communication between immune cells but is a T cell mediator that directly promotes the innate, nonspecific immunity of tissues.

No abstract

The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.

Neutralization of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) or interleukin-1 (IL-1), decreases mortality in several animal models of sepsis. However, recent clinical trials did not show an unequivocal improvement in survival. In contrast to animals, which succumb to shock during the first 72 hours, we found that many patients die much later with signs of opportunistic infections accompanied by downregulation of their monocytic HLA-DR expression and reduced ability to produce lipopolysaccharide (LPS)-induced TNF-alpha in vitro. This phenomenon of monocyte deactivation in septic patients with fatal outcome shows similarities to experimental monocytic refractoriness induced by LPS desensitization or by pretreatment with its endogenous mediators IL-10 and transforming growth factor-beta (TGF-beta). In order to strengthen their antimicrobial defense, here we tested whether interferon-gamma (IFN-gamma) can improve monocytic functions in these patients and in experimental monocytic deactivation. The considerably lowered in vitro levels of LPS-induced TNF-alpha in these situations were significantly enhanced by IFN-gamma, but did not reach the extremely high levels of IFN-gamma primed naive cells from healthy donors. Moreover, IFN-gamma applied to septic patients with low monocytic HLA-DR expression restored the deficient HLA-DR expression and in vitro LPS-induced TNF-alpha secretion. Recovery of monocyte function resulted in clearance of sepsis in eight of nine patients. These data suggest that IFN-gamma treatment in carefully selected septic patients is a novel therapeutic strategy worth pursuing.

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.

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This study investigated the expression of five novel human IL-10-related molecules and their receptors in blood mononuclear cells. IL-19 and IL-20 were found to be preferentially expressed in monocytes. IL-22 and IL-26 (AK155) expression was exclusively detected in T cells, especially upon type 1 polarization, and in NK cells. IL-24 (melanoma differentiation-associated gene 7) expression was restricted to monocytes and T cells. Detection of these molecules in lymphocytes was predominantly linked to cellular activation. Regarding T cells, IL-26 was primarily produced by memory cells, and its expression was independent on costimulation. In contrast to the high expression of receptors for IL-10 homologs in different tissues and cell lines, monocytes and NK, B, and T cells showed clear expression only of IL-10R1, IL-10R2, and IL-20R2. In these cells, IL-20R2 might be part of a still-unknown receptor complex. Therefore, immune cells may represent a major source but a minor target of the novel IL-10 family members.

Glucocorticoids (GCs) are the most commonly used antiinflammatory and immunosuppressive drugs. Their outstanding therapeutic effects, however, are often accompanied by severe and sometimes irreversible side effects. For this reason, one goal of research in the GC field is the development of new drugs, which show a reduced side-effect profile while maintaining the antiinflammatory and immunosuppressive properties of classical GCs. GCs affect gene expression by both transactivation and transrepression mechanisms. The antiinflammatory effects are mediated to a major extent via transrepression, while many side effects are due to transactivation. Our aim has been to identify ligands of the GC receptor (GR), which preferentially induce transrepression with little or no transactivating activity. Here we describe a nonsteroidal selective GR-agonist, ZK 216348, which shows a significant dissociation between transrepression and transactivation both in vitro and in vivo. In a murine model of skin inflammation, ZK 216348 showed antiinflammatory activity comparable to prednisolone for both systemic and topical application. A markedly superior sideeffect profile was found with regard to increases in blood glucose, spleen involution, and, to a lesser extent, skin atrophy; however, adrenocorticotropic hormone suppression was similar for both compounds. Based on these findings, ZK 216348 should have a lower risk, e.g., for induction of diabetes mellitus. The selective GR agonists therefore represent a promising previously undescribed class of drug candidates with an improved therapeutic index compared to classical GCs. Moreover, they are useful tool compounds for further investigating the mechanisms of GR-mediated effects.inflammation ͉ nuclear receptor ͉ dissociated glucocorticoid receptor ligand