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Recently, we could show that IL-31 serum levels are significantly increased in adult patients with atopic dermatitis compared with skin healthy controls. However, the regulation of IL-31 in children with atopic dermatitis so far is not clear. Thus, we analyzed IL-31 serum levels together with IL-4, IL-13, ECP, and total IgE levels in 60 children with extrinsic, in five children with intrinsic atopic dermatitis, and 20 non-atopic healthy children. Further, we determined the SCORAD score, sleeplessness, and pruritus severity in all children with atopic dermatitis. IL-31 was significantly increased in children with the intrinsic and extrinsic type of atopic dermatitis compared with non-atopic healthy children (p < 0.05-0.001). Further, IL-31 serum levels significantly correlated with SCORAD score (p < 0.01), sleeplessness (p < 0.05), IL-4, and IL-13 levels (p < 0.01) in children with extrinsic atopic dermatitis. There was no correlation of IL-31 with pruritus, total IgE Ab, and ECP levels, whereas ECP levels significantly correlated with the SCORAD score in children with extrinsic atopic dermatitis. Together, IL-31 represents an interesting cytokine especially with regard to the severity of the inflammatory process indicated by the correlation of IL-31 with SCORAD score and Th2 cytokines including IL-4 and IL-13 in children with extrinsic atopic dermatitis., (© 2011 John Wiley & Sons A/S.)

Bullous pemphigoid (BP) is characterized by substantial skin and blood eosinophilia as well as intensive pruritus. Since the pruritogenic cytokine interleukin (IL)-31 is increased in inflammatory skin diseases the aim of this study was to determine whether IL-31 plays a role in BP. Using immunofluorescence, IL-31 expression was analysed in eosinophils derived from blister fluids and skin from patients with BP and IL-31 levels in blister fluids, serum and culture supernatants were determined by enzyme-linked immunoassay (ELISA). High levels of IL-31 expression were observed in BP blister fluids, but they were only marginally elevated in BP serum compared with healthy controls. Eosinophils from either BP blister fluids or skin biopsies showed strong expression of IL-31. Furthermore, peripheral blood eosinophils from patients with BP, but not healthy controls, released high levels of IL-31, reflecting those in blister fluids. In conclusion, eosinophils are a major source of IL-31 in BP and this cytokine may contribute to itch in patients with BP. [ABSTRACT FROM AUTHOR]

Chronic skin ulcers, such as leg ulcers, pressure sores and diabetic foot ulcers, are a challenge to physicians and medical personnel and a cause of tremendous discomfort and ensuing loss of quality of life to the patients. Wound healing involves production and action of various growth factors. A novel approach, distinct from the application of single growth factors, is the administration of the macrophage stimulator macrophage-activating lipopeptide-2 (MALP-2). The rationale is based on the finding that macrophages are the main source of several growth factors required for wound healing, which are sequentially released during this process. MALP-2 has previously been shown to be effective in an established animal model with diabetic mice. The purpose of the present phase I study was to establish tolerability of MALP-2 when applied into small cutaneous wounds in human beings. Twelve patients (six females and six males; mean age 66.8 years; range 52–87 years) with different diagnoses were enrolled into the study. An artificial wound was created with a 2-mm diameter skin biopsy punch and a volume of 30 μl MALP-2 (0.125–1 μg) or vehicle control, respectively, was injected intracutaneously into the wound and closed with a water-resistant transparent adhesive. Photos were taken daily from every patient up to 6 days, and skin biopsies were performed after 1 week from six patients. We could show in the present study for the first time that MALP-2 caused a transient erythema and was tolerated without any systemic side effects up to a dose of 1 μg per wound in human beings. In healthy as well as in diabetic patients, MALP-2 induced local inflammation that faded after 48 h. The effectiveness of MALP-2 in the healing of chronic wounds in humans, e.g. in chronic skin ulcers, such as leg ulcers, pressure sores and diabetic foot ulcers, could now be addressed in further studies. [ABSTRACT FROM AUTHOR]

We undertook a study to determine whether cytokines exist which are responsible for the activation of polymorpho-nuclear neutrophilic granulocytes (PMN) besides the already well-known stimuli. Lucigenin-dependent chemiluminescence was used to measure human PMN activation. Addition of supernatants from mononuclear cells stimulated with bacterial lipopolysaccharide produced a long-lasting activation of granulocytes. Induction of chemiluminescence was dose-dependent and inhibitable by superoxide dismutase. Fractionation of mononuclear cells by adherence to plastic dishes or counterflow elutriation proved that monocytes were able to generate granulocyte-activating mediators (GRAM). Production of GRAM was dependent on the dose of the stimulus and appeared to be maximal alter 24 h of incubation. Addition of cycloheximide resulted in significantly decreased release of GRAM. Partial characterization of the activity showed GRAM to be heat-labile and sensitive to trypsin, indicating a protein nature of GRAM. The activity fractionated into 2 distinct peaks, one corresponding to 60 kD and another below 10 kD. The interleukin 1 activity did not appear to cofractionate with GRAM. Evidence presented suggests that the activity corresponds to factors unlikely to have been described previously. [ABSTRACT FROM AUTHOR]

Human dermal mast cells are capable of releasing cytokines, particularly preformed TNFα, upon appropriate stimulation. Mast cell activation in vivo was shown to be associated with an influx and activation of inflammatory cells, initially PMN (polymorphonuclear neutrophilic granulocytes) then eosinophils. In order to learn more about the mechanisms by which TNFα is capable of activating eosinophils, in the present study the effect of TNFα on morphology and function of highly purified normal eosinophils ( ≥ 95%) was examined. As estimated by transmission and scanning electron microscopy, TNFα-stimulated eosinophils appeared to be strictly adherent and flattened exhibiting a characteristic "hemispheric" shape. TNFα induced a dose-dependent, long-lasting production of reactive oxygen species as measured by lucigenin-dependent chemiluminescence (CL), even at a concentration of 0.001 U/mI. The maximal response upon stimulation with TNFα, however, was significantly lower than optimal effects induced by IL-5. TNFα- induced responses were completely inhibited by cytochalasin B and staurosporin, and partially blocked by pertussis toxin. Separation of eosinophils by discontinuous density gradients revealed the existence of at least two hypodense eosinophil populations with a distinct susceptibility to stimulation with TNFα. Based on functional assay systems, in contrast to a significant extracellular, only a small intracellular H[SUB2]O[SUB2] production was detected. Accordingly, H[SUB2]O[SUB2] production, detected by an ultrastructural technique, was observed only on the outer surface of the plasma membrane in the contact zones in between adjacent cells. [ABSTRACT FROM AUTHOR]

A soluble form of the usually membrane-bound adhesion molecule ICAM-1 was detected in supernatants derived from human epidermal keratinocytes. Specifically, supernatants harvested from long-term cultured normal hytotoxiciuman keratinocytes, or from the spontaneously immortalized keratinocyte cell line HaCaT, did not contain significant amounts of sICAM-1, but shedding of sICAM-1 was found to be markedly induced upon stimulation of keratinocytes with rh IFNγ. In contrast, cells from the two epidermoid carcinoma cell lines. KB and A431, constitutively shed significant amounts of sICAM-1 even without cytokine stimulation, and sICAM-1 contents in supernatants harvested from these cells were further increased upon stimulation of cells with rh IFNγ. These studies indicate, that in addition to peripheral blood mononuclear cells and human melanoma cells, human epidermal keratinocytes constitute an important cellular source of sICAM-1. By binding to leukocyte LFA-1 molecules, keratinocyte-derived sICAM-1 may influence inflammatory responses in the skin. In addition, constitutive shedding of sICAM-1 by transformed human keratinocytes may represent a possible mechanism by which neoplastic keratinocytes escape from cytotoxicity. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Increased levels of serum IL-31 in chronic spontaneous urticaria. Experimental Dermatology 2010; 19: 464–466. IL-31 represents a novel cytokine involved in pruritic skin diseases including atopic dermatitis (AD). We, therefore, aimed at investigating IL-31 levels in chronic spontaneous urticaria (CU). We included 46 patients with CU, 26 non-atopic skin healthy subjects as negative and 28 patients with AD as positive controls. IL-31 serum levels were analysed using commercial ELISA kit. IL-31 serum levels were higher in patients with CU compared to healthy controls ( P < 0.001), but lower compared to patients with AD ( P < 0.001). There was no difference in IL-31 serum levels in autologous serum skin test positive or negative CU patients and patients with infectious trigger factors including helicobacter pylori infection. IL-31 serum levels may play a role in the pathophysiology of CU. This is supported by the finding that not all patients with CU respond to antihistamine treatment but to the treatment with immunosuppressive drugs. [ABSTRACT FROM AUTHOR]

Examines the cytokine profile expressed in acute versus spontaneous allergic contact dermatitis lesions on the mRNA and protein level. Presence of T lymphocytes in allergic inflammation; Importance of T lymphocytes; Characteristic for acute lesions of atopic dermatitis.

Compares eosinophil (EOS) survival and apoptosis in nonatopic volunteers and in patients with inhalant allergy or acute exacerbation of atopic dermatitis. Cytokines that support EOS survival and delay apoptosis; Use of the ELISA technique.

The majority of allergen-specific T cells derived from inhalant allergen patch test lesions in patients with atopic dermatitis were previously found to produce a restricted type-2 cytokine pattern. Recent studies, however, have revealed that in chronic eczematous skin lesions of patients with atopic dermatitis, expression of the type-1 cytokine interferon-y predominates. To evaluate cytokine production by allergen-specific T cells in chronic atopic dermatitis, we established house dust mite (Dermatophagoides pteronyssinus)-specific T-cell clones from the dermis of chronic skin lesions of sensitized adult patients with atopic dermatitis. Frequencies of skin-derived T cells proliferating in the presence of Dermatophagoides pteronyssinus were between one in 138 and one in 4255, indicating that only a minority of skin-infiltrating T cells are allergen specific. When these cells were analyzed for their capacity to produce interferon-γ, the majority (71%) of these cells were found to express interferon-γ mRNA and to secrete interferon-γ protein, either alone or in combination with interleukin-4. Phenotypic analysis revealed that 15% of skin-infiltrating allergen-specific T cells were CD8+. No selection of Vβ elements was detected in Dermatophagoides pteronyssinus-specific T-cell clones. These studies demonstrate that allergen specificity of skin-infiltrating T cells is not restricted to a type-2 cytokine pattern in lesional atopic dermatitis. The notion that the majority of allergen-specific, skin-infiltrating T cells are capable of producing interferon-γ further supports the concept that interferon-γ expression has major pathogenetic relevance for the chronic phase of atopic dermatitis. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor α (TNFα) is a potent modulator of human keratinocyte intercellular adhesion molecule-1 (ICAM-1) expression. TNFα is known to exert its biologic effects by binding to specific cell-surface receptors. Two distinct TNF binding molecules, the 55-kd and the 75-kd TNF receptor (TNFR) recently have been found to be expressed by human cells. These two receptor types are independently regulated and differ markedly in their intracellular regions, indicating functional dichotomy. In order to gain further insight into the mechanisms underlying ICAM-1 regulation in human keratinocytes, in the present study, the receptor molecules mediating TNFα induced ICAM-1 upregulation in human keratinocytes was defined. Human keratinocyte TNFR expression was assessed using monoclonal antibodies that specifically recognize the 55-kd or the 75-kd TNFR. Using FACS analysis, normal (HNK) as well as transformed (KB) human keratinocytes were found to react with anti - 55-kd TNFR, but not anti - 75-kd TNFR antibodies. These immunofluorescence data were confirmed by Northern blot analysis revealing clearly detectable amounts of mRNA specific for the 55-kd TNFR in KB cells. Incubation of human keratinocytes with anti - 55-kd TNFR antibodies at 37°C for 24 h increased ICAM-1 expression in a TNFα-like fashion. Moreover, the well known synergistic effect of IFNγ plus TNFα on keratinocyte ICAM-1 induction could be mimicked by stimulation of cells with IFNγ plus anti - 55-kd TNFR antibodies. Synergistic ICAM-1 induction was not associated with increased expression of the 55-kd TNFR in IFNγ-stimulated human keratinocytes. These studies indicate that human keratinocytes express the 55-kd TNF receptor and that this surface molecule may play an important role in regulation of human keratinocyte ICAM-1 expression. [ABSTRACT FROM AUTHOR]