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Interleukin (IL)-10 is an important immunoregulatory cytokine that mediates its effects via a transmembrane receptor complex consisting of two different chains, IL-10R1 and IL-10R2. While IL-10R2 is ubiquitously expressed and does not bind IL-10 primarily, the expression of IL-10R1 determines cellular responsiveness. However, the current knowledge about the expression and regulation of IL-10R1 is still limited. Here we analyzed the expression of IL-10R1 on monocytic cells and demonstrated that human blood monocytes carried about 720 IL-10-binding sites on their surface. Compared with lymphocytes and various tissue cells and tissues, blood monocytes expressed the highest IL-10R1 levels. The in vitro differentiation of these cells into macrophages provoked a further increase of IL-10R1 surface expression. In contrast, their differentiation into myeloid dendritic cells (mDCs) resulted in reduced surface IL-10R1 levels. The different IL-10R1 levels expressed by monocyte-derived antigen-presenting cell populations were reflected in their different responsiveness toward IL-10. Importantly, also in vivo developed immature macrophages and mDCs showed different IL-10 sensitivity. These data suggest that, compared with monocytes and macrophages, mDCs partially escape from IL-10's inhibitory mechanisms by downregulating IL-10R1.

Interleukin-10 is an important anti-inflammatory and immunosuppressive cytokine with major impact on several immune reactions, including regulatory mechanisms in the skin. Recently, we performed a phase II trial in psoriatic patients receiving subcutaneously interleukin-10 over 7 wk. The clinical response suggested that interleukin-10 might represent a novel anti-psoriatic drug. In order to understand better the mode of action and to elucidate the effects of systemic interleukin-10 treatment on the skin immune system, skin punch biopsies from sites different from interleukin-10 injection were analyzed. Biopsies were obtained from the patients before, at the end, and 3 wk after interleukin-10 therapy. The results are reported here. Histologic examination showed a decrease of several parameters reflecting the psoriatic disease activity as acanthosis and extension of the horny layer. Immunohistologic examination demonstrated decreasing numbers of infiltrating T cells, dermal CD1a+ cells, and a diminished proliferation of epidermal cells. Using a novel, quantitative reverse transcriptase-polymerase chain reaction approach a significant shift within the cytokine pattern was found. Interleukin-10 therapy led to a decrease of cutaneous interleukin-8 and interleukin-10 mRNA expression. Whereas no significant changes of interleukin-6, tumor necrosis factor-alpha, and interferon-gamma expression were found, interleukin-4 was strongly upregulated suggesting a shift from a type 1 towards a type 2 cytokine pattern. The changes within the local cytokine pattern seem to be disease-related, as an inverse course was found in a single interleukin-10 nonresponding patient. Our findings demonstrate considerable effects of systemic interleukin-10 application on the skin immune systems, which might contribute to the anti-psoriatic activity of interleukin-10.

The anti-inflammatory cytokine IL-10 is up-regulated in response to TNF-alpha suggesting a control mechanism of inflammation. In addition, we recently found systemic IL-10 release in response to acute stress reactions in the absence of any systemic inflammation. In vitro and in vivo studies in experimental models suggest that catecholamines induce IL-10 release via a cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) dependent pathway. Here we studied patients for plasma IL-10 after acute myocardial infarction, a very stressful event without significant signs of systemic inflammation. In fact, the activation of the sympathetic system initiated by cardiac infarction was accompanied by a temporary systemic release of IL-10. Catecholamine induced IL-10 may be released by different cells. Recently, we demonstrated that catecholamines directly stimulate the IL-10 promoter/enhancer via a cAMP/PKA pathway in monocytic cells. A cAMP responsive element (CRE) was identified as major target. Here we show that there is no influence of catecholamines on the IL-10 promoter activity in T-cells. In contrast to monocytic cells, in T-cells cAMP-induced PKA-dependent phosphorylation of the CRE-binding protein 1 (CREB-1) seems to play a marginal role in IL-10 induction, which was reflected by a low cAMP-dependent IL-10-promoter/enhancer stimulation in reporter gene assays. Thus, catecholamines are directly involved in the regulation of IL-10 expression in monocytic but not in T-cells after acute stressful conditions.

Background: In patients with alcoholic liver cirrhosis, endotoxaemia is a frequent finding. Unknown mechanisms, however, prevent typical clinical symptoms of endotoxaemia in many patients., Methods: We determined plasma levels of pro- and anti-inflammatory mediators, ex vivo cytokine secretion capacity, and expression of tumour necrosis factor (TNF) receptors on phagocytic blood cells in 49 patients with alcoholic cirrhosis and 41 age matched healthy controls., Results: In addition to increased levels of proinflammatory cytokines in cirrhotic patients, we observed consistent upregulation of the anti-inflammatory mediators interleukin 10 (IL-10) (plasma 15.75 (1. 6) v 6.6 (1.3) pg/ml (p<0.001); ex-vivo 108.4 (22.0) v 40.1 (7.4) pg/ml (p<0.05)), interleukin 1 receptor antagonist (plasma 527.1 (83) v 331.4 (56) pg/ml (p<0.05); ex vivo 19.9 (3.4) v 10.2 (2.7) ng/ml (p<0.01)), and soluble TNF receptors (sTNF-R) in plasma (sTNF-RI 3157.2 (506.2) v 607.9 (300.3) pg/ml; sTNF-RII 3331.0 (506. 2) v 1066.4 (225.1) pg/ml (p<0.001 for both)). Desensitisation at the target cell level was indicated by reduced expression of TNF receptor I on granulocytes (64.8 (6.5) v 40.1 (7.3)% positive cells; p<0.05) and unaltered plasma levels of soluble E-selectin., Conclusion: In patients with alcoholic liver cirrhosis, upregulation of the pro- and anti-inflammatory cytokine system and simultaneous desensitisation of effector cells could explain the restricted systemic inflammatory response to chronic endotoxaemia. This alteration in immune status may lead to impairment of host defences against infections which are frequent complications of alcoholic cirrhosis.

By virtue of its anti-inflammatory and immunosuppressive properties, IL-10 plays a crucial role in several immune reactions, including regulatory mechanisms in the skin. In psoriasis, a common cutaneous immune disease, a relative deficiency in cutaneous IL-10 expression is observed. Several lines of evidence suggest that IL-10 could have antipsoriatic abilities. One pilot and two Phase II trials with sc. IL-10 administration over 3 - 7 weeks in patients with moderate to severe psoriasis have supported this hypothesis. The therapy was well-tolerated and clinical efficiency was found in the majority of patients. Immunosuppressive effects (depressed monocytic HLA-DR expression, TNF-alpha and IL-12 secretion capacity, IL-12 plasma levels and responsiveness to recall antigens) as well as a shift towards a Type 2 cytokine pattern (increasing proportion of IL-4, IL-5, and IL-10 producing T-cells, selective increase in IgE serum levels) were observed. These investigations suggest that IL-10 is of major importance in psoriasis and show that IL-10 administration represents a new therapeutic approach. However, long-term administration of large recombinant protein limits the value of this novel therapeutic approach. As such, neither oral nor topical applications are possible; there is a risk of the development of neutralising antibodies.

With its antiinflammatory and immunosuppressive properties interleukin-10 (IL-10) plays a dominant role in several immune reactions including regulatory mechanisms in the skin. The overexpression of this mediator has been reported in some inflammatory dermatoses as well as in various skin tumors. These observations are of importance since they may explain the limitation of hyperinflammatory conditions as in eczemas and erythemas on the one hand and the suppression of an adequate antitumor response and thereby the progression of malignant tumors on the other hand. Moreover, elevated IL-10 expression might contribute to an enhanced risk of development of microbacterial superinfections, a frequent finding in several dermatoses, and might also be involved in the pathogenesis of connective tissue diseases. In contrast, recent studies indicate a relative IL-10 deficiency in psoriasis. Early clinical data from psoriatic patients treated with recombinant human IL-10 suggest the therapeutic potential of this cytokine and underline its impact on the regulation of the skin immune system.

Objective: To determine the safety and clinical effects of interleukin 10 (IL-10) treatment of psoriasis., Design and Methods: In an open-label phase 2 trial, 10 patients with psoriasis subcutaneously received recombinant human IL-10 over a 7-week period in a dosage of 8 microg/kg daily (n=5) or 20 microg/kg 3 times per week (n=5). Patients were followed up for an additional 5 weeks., Results: The treatment was well tolerated. Antipsoriatic effects were found in all but 1 patient. A significant decrease of the psoriasis area and severity index by 55.3% +/- 11.5% (mean +/- SEM) was observed (P<.02). The antipsoriatic efficiency was confirmed by histological examination. Heterogeneity in the effectiveness was found among the patients, but seems to be independent of the dosage regimen. However, a tendency to a better response was found in the patients who received 20-microg/kg IL-10 3 times per week. Decreasing response in the delayed-type hypersensitivity reaction against recall antigens indicated immunosuppressive effects. Moderate effects on hematopoietic cells were observed., Conclusions: Our data suggest that IL-10 therapy for psoriasis is safe and possibly clinically effective. Consequently, its value in psoriasis and similar immune diseases should be further determined. Dose-finding, placebo-controlled, double-blind trials are necessary now.

In recent years the investigation of cytokines has been a focus of scientific interest in order to understand the pathogenesis of a variety of diseases. In additions cytokines are increasingly being used for therapeutic purposes, including dermatologic disorders. IL-10 is a recently described cytokine with anti-inflammatory and immunosuppressive qualities which plays an important role in immunoregulation. The overexpression of this mediator has been proven in some inflammatory dermatoses as well as in various skin tumors. These observations help to understand down regulatory events in hyper-inflammatory conditions such as allergic or toxic dermatitis on the one hand and the suppression of an adequate anti-tumor response and thereby the progression of malignant tumors on the other hand. Recent investigations indicate a relative IL-10 deficiency in psoriasis. Initial therapeutic applications of IL-10 in psoriasis underline the pathophysiological importance of this cytokine.

The mechanism of immunodepression after brain injury is not yet clear. Here we demonstrate rapid systemic release of the immunoinhibitory cytokine interleukin-10, monocytic deactivation and a high incidence of infection in patients with 'sympathetic storm' due to acute accidental or iatrogenic brain trauma. In vitro studies showed that within minutes catecholamines trigger the secretion of interleukin-10 from unstimulated monocytes through a beta-adrenoreceptor-mediated, cAMP/protein kinase A-dependent pathway. We found that in a rat model of acute brain injury, the beta-receptor antagonist propranolol prevented the increase of interleukin-10 plasma levels. Rapid monocytic interleukin-10 release after sympathetic activation may represent a common pathway for immunodepression induced by stress and injury.

Overexpression of proinflammatory, type 1 cytokines has been demonstrated in psoriasis and is believed to be of pathophysiological importance. IL-10 is a type 2 cytokine with major impact on immunoregulation, since it inhibits type 1/proinflammatory cytokine formation. Therefore, we investigated its role in psoriasis. We found a relative deficiency in cutaneous IL-10 mRNA expression compared with other inflammatory dermatoses. Interestingly, patients during established antipsoriatic therapy showed higher IL-10 mRNA expression of peripheral blood mononuclear cells than patients before therapy. This suggested that IL-10 may have antipsoriatic capacity. Therefore, we performed a phase 2 pilot trial with subcutaneous IL-10 administration (8 microg/kg/d) over 24 d in three patients. Clinical efficiency measured by objective and subjective parameters was found. Immunosuppressive effects (depressed monocytic HLA-DR expression, TNF-alpha and IL-12 secretion capacity, IL-12 plasma levels, and responsiveness to recall antigens) as well as a shift toward a type 2 cytokine pattern (increasing proportion of IL-4, IL-5, and IL-10 producing T cells, selective increase in IgE serum levels) were observed. Remarkably, IL-10 administration also enhanced the intracutaneous IL-10 mRNA expression. Our investigations demonstrate the major importance of IL-10 in psoriasis and show that IL-10 administration represents a new therapeutic approach. This is the first report on IL-10 therapy for cutaneous disorders.

Cytokines are believed to play an important role in the pathogenesis of cutaneous T cell lymphoma. Data regarding the local cytokine pattern in mycosis fungoides (MF) are partly conflicting. Recent studies have suggested a shift from type 1 to type 2 cytokine pattern because IL-4 and IL-5 mRNA have been more frequently detected in lesions of advanced stages. Another study has described a type 1 cytokine pattern in MF lesions. None of the previous studies of cytokine mRNA expression in MF, however, used quantitative methods, and therefore only the presence of a cytokine, but not the level of expression, could be determined. To gain better insight into the development of cytokine pattern during tumor progression we used semiquantitative reverse transcriptase-polymerase chain reaction to analyze cytokine mRNA expression in MF skin lesions at different stages. Biopsies from patients with patch (n = 11), plaque (n = 6), and tumor (n = 3) stage MF were compared with biopsies from patients with pleomorphic T cell lymphoma (n = 5), psoriasis (n = 7), atopic dermatitis (n = 5), and nonlesional skin (n = 8). MF progression was associated with significantly higher IL-10 and lower interferon-gamma mRNA expression. Moreover, the stage-dependent increase in IL-10 mRNA expression was also found in paired samples from individual patients. Unlike in pleomorphic T cell lymphoma, however, typical T helper 2 cells did not seem to be the source of increasing IL-10 in advanced MF, because stage-independent IL-4 mRNA was rarely detected, suggesting contribution of nonlymphoid cells to local IL-10 production. The overexpression of IL-10 in MF may be of importance for tumor progression, because this immunosuppressive cytokine might be involved in downregulation of immunologic tumor surveillance.