Lajos Kemény

HHV8 DNA IN ANGIOLYMPHOID HYPERPLASIA OF THE SKIN

1986-89 recorded an incidence of 0-7% of failed treatment in patients initially sputum positive-ie, still sputum positive after 6 months of chemotherapy. The default rate was 17-8% over one year. Many patients had previous treatment in other camps, but they rarely admitted it. There was no HIV infection in Somalia at the time. Recreational drug consumption in Somalia was limited to harmless Xat. In the

Pyodermatitis-pyostomatitis vegetans

A 43‐year‐old woman developed annular and pustular cutaneous lesions preceded by tiny yellow pustules coating the surface of the oral mucosa. The clinical, histological and immunopathological evidence clearly showed that the patient had pyodermatitis–pyostomatitis vegetans. It is suggested that this disease is a distinct entity which should be differentiated from pemphigus vegetans.

Effects of the Neuropeptides Substance P, Calcitonin Gene-Related Peptide and α-Melanocyte-Stimulating Hormone on the IL-8/IL-8 Receptor System in a Cultured Human Keratinocyte Cell Line and Dermal Fibroblasts

The neuropeptides substance P (SP), calcitonin gene-related peptide (CGRP) and α-melanocyte-stimulating hormone (α-MSH) are known to be able to regulate the production of cytokines in the skin. Since IL-8 plays an important role in cutaneous inflammation, the effects of SP, CGRP and α-MSH on the IL-8/IL-8 receptor (IL-8RA) systems of these cell types were studied. Cultures of human dermal fibroblasts and an immortalized keratinocyte cell line HaCaT were treated with 10−8 M SP, CGRP or α-MSH. The results demonstrated that these neuropeptides have different effects on the IL-8 and IL-8RA expressions of the cells. SP and CGRP upregulated the IL-8RA mRNA expression in HaCaT cells, but had no influence on their IL-8 production, whereas, α-MSH had no effect on either the IL-8 or the IL-8RA mRNA expression in HaCaT cells. In contrast, α-MSH resulted in a time-dependent induction of the IL-8 mRNA expression in dermal fibroblasts. This induction was already detectable after 6 h, and after 12 h there was a 5-fold change in comparison with the controls. The IL-8 content of the supernatant was also increased, with a maximum at 48 h after α-MSH treatment. The data established in the present study support the notion that neuropeptides can directly modulate the IL-8/IL-8RA system of keratinocytes and fibroblasts.

Role of lnterleukin-8 Receptor in Skin

Interleukin-8 (IL-8) is a potent chemotactic and proinflammatory cytokine, produced in the skin by a variety of cells in response to inflammatory stimuli. Recent studies suggest that in addition to its potent actions on leukocytes, IL-8 exerts a direct influence on several functions of human epidermal cells such as chemotaxis, Candida albicans killing activity or proliferation. The effects of IL-8 are mediated by binding to two types of specific high-affinity receptors which contain seven transmembrane domains typical of guanine nucleotide binding protein (G protein)-coupled receptors. In the skin, a broad spectrum of cells such as neutrophils, T lymphocytes, mast cells, dermal macrophages, endothelial cells and keratinocytes possess binding sites for IL-8. Recently, increased expression of epidermal IL-8 receptors has been observed in psoriasis an inflammatory and hyperproliferative skin disease. Since the effects of IL-8 may be modulated at the receptor level, the pharmacological manipulation of the IL-8 receptor may prove an important target for the therapy of skin diseases with increased IL-8 levels.

Chemotaxis of freshly separated and cultured human keratinocytes

It is generally accepted that keratinocyte migration plays a critical role in the process of wound healing. A study was therefore made of the migratory response of freshly separated and cultured human keratinocytes to factors with chemotactic properties for a variety of cells. Interleukin‐lα (IL‐lα), interferon‐γ (IFN‐γ), interleukin‐8 (IL‐8), and tumour necrosis factor α (TNF‐α) were tested for their chemotactic effectiveness in a modified Boydcn chamber assay. IFN‐γ, IL‐lα and IL‐8 were demonstrated to serve as chemoattractants for freshly separated keratinocytes. For cultured cells, however, only IFN‐γ was found to display chemotactic properties. The findings demonstrate that there is significant difference between the chemotactic behaviour of freshly separated and cultured cells.

Cytokine system as potential target for antipsoriatic therapy.

Abstract Cytokines are produced by a variety of cells and have numerous of overlapping activities. There is increasing evidence that cytokines play a crucial role in the pathogenesis of psoriasis and of other dermatologic diseases. This review summarizes current knowledge as to how the altered cytokine network is involved in the accumulation of inflammatory cells in lesional skin, and how the cytokines are involved in epidermal hyper‐proliferation. The actions of the most important therapeutic compounds, such as corticosteroids, dithranol, cyclosporine, retinoids, vitamin D3 analogues and ultraviolet radiation, on the cytokine system are also discussed. Consideration is given as to how the effects on the production of cytokines and/or cytokine receptors contribute to their therapeutic action.

The interleukin-8 receptor: a potential target for antipsoriatic therapy?☆

Interleukin-8 is assumed to play a central role in the pathogenesis of psoriasis. Since an increased expression of the interleukin-8 receptor has been observed both in polymorphonuclear leukocytes and in affected psoriatic epidermis, we were interested in whether the interleukin-8 receptor could be a molecular target of antipsoriatic compounds. Cyclosporine, calcitriol, calcipotriol or dithranol caused a dose-dependent decrease in interleukin-8 binding to cultured human keratinocytes, while interleukin-8 binding to granulocytes was not affected. In addition, the interleukin-8-induced human leukocyte antigen-DR (HLA-DR) expression of keratinocytes was nearly completely blocked by treatment of the cells with these substances. The inhibition of the keratinocyte interleukin-8 receptor and its function by antipsoriatic drugs may contribute to their therapeutic action.

Skin lesions as the only manifestation of the hypereosinophilic syndrome.

produce cytokines that mediate tissue damage. Tbie cytotoxicity of these hydroxylamine derivatives diminishes after coincubation with glutathione or NAC.̂ NAC reacts with reactive oxidative intermediates and replenishes intraceiluiar cysteine ieveis necessary for the production of giutathione. Intracelluiariy, glutathione is the dominant thiol, acting as an antioxidant. Furthermore, NAC inhibits nuclear factor KB (NFKB),^ a transcription factor induced hy TNF-a, tL-l and oxygen derivatives such as hydrogen peroxide. NFKB is involved in the transcription of several genes, coding for the IL-2 receptor achain, and interferon-7.^^ tn this way, we have demonstrated in vitro that NAC inhibits production of TNF-a and IL-1/3, implicated in the pathogenesis of TEN. ̂ ^ and possibly in other toxic drug reactions. We have also reported one patient affected with TEN who was succesfuUy treated with intravenous NAC, S-adenosyl-Lmethionine (SAM, a glutathione precursor) and pentoxifylline.^^ In that report improvement was attributed to pentoxifylline, although it is possible that NAC and SAM were therapeutically more important than we thought. Other anti-inflammatory effects of NAC, antagonizing development of irritant and contact hypersensitivity reactions,^* and modulating ICAM-1 expression in human keratinocytes,^ have been described. NAC has been administered in pulmonary disorders as an expectorant, and in acetaminophen overdose. NAC is a nontoxic drug with well-documented pharmacokinetics and safety, ̂ ^ that might be effective in high-dose intravenously for 4 6 days, in HS and TEN by two means: replenishing cells with antioxidant capacity and inhibiting cytokine mediated immune reactions. Further study is required to confirm the therapeutic effect of NAC in toxic drug reactions.

Identification of a soluble interleukin-8 inhibitor in the supernatant of polymorphonuclear leukocytes

Interleukin-8 (IL-8) plays a crucial role in the pathogenesis of inflammatory and hyperproliferative diseases in various organs. The purpose of the present investigation was to establish whether there is any naturally occurring inhibitor of IL-8. Here we demonstrate that an IL-8 inhibitor (IL-8INH) is present in the supernatant of polymorphonuclear (PMN) leukocytes. The release of IL-8INH could be increased by stimulating the PMN leukocytes by concanavalin A. IL-81NH blocks the IL-8-induced chemotaxis and Candida albicans killing activity of PMN leukocytes and epidermal cells in vitro, and IL-8-induced neutrophil infiltration in the mouse ear in vivo. The mechanism of action of IL-8INH involves blocking of 125I-IL-8 binding to the IL-8 receptor. Binding of 125I-IL-8 to neutrophils could not be displaced by the IL-8INH, however, preincubation of 125I-IL-8 with IL-8INH increased binding inhibition, suggesting an interaction between IL-8 and the inhibitor. Crosslinking of 125I-IL-8 to IL-8INH shows that IL-8INH binds specifically to 125I-IL-8, and the IL-8INH protein has an apparent molecular weight of 52 kDa in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The partial purification of the IL-8INH on DEAE-Sephadex anion-exchange chromatography column also suggests a 50-60-kDa inhibitor protein which blocks IL-8-induced effects on neutrophils by binding to IL-8.

Effect of BN 52021, a platelet activating factor antagonist, on dithranol-induced inflammation

The effect of BN 52021, a selective platelet activating factor (PAF) antagonist was studied on dithranol‐induced irritant dermatitis. Pretreatment of the skin with 0.45% BN 52021 ointment significantly suppressed the decrease in capillary resistance, rise in skin temperature and increase in skin‐fold thickness produced by dithranol.