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Notes: Summary Cutaneous atrophy arising from prolonged use of potent topical corticosteroids has long been a concern. Thus, it would be advantageous to find an agent which protects against atrophy produced by corticosteroids but at the same time does not impair their anti-inflammatory effects. Recent work shows that topical all-trans retinoic acid (tretinoin) prevents skin atrophy in mice treated with topical corticosteroids, but such studies have not been performed in humans. We performed an 8-week clinical, histological and biochemical study to test the ability of tretinoin to enhance efficacy and inhibit atrophogenicity of topical corticosteroids, when used in the treatment of psoriasis. In each of 20 psoriasis patients, one plaque, and its perilesional skin, was treated once daily with betamethasone dipropionate and tretinoin 0·1%, and one plaque, and its perilesional skin, treated with once daily betamethasone dipropionate and tretinoin vehicle. There was no difference in the speed or degree of improvement in plaques treated with either the topical corticosteroid/tretinoin combination or with corticosteroid alone. Light microscopy revealed a 19% reduction in epidermal thickness, in corticosteroid-treated perilesional skin, as compared with a slight (1%) increase in corticosteroid/ tretinoin-treated perilesional areas (P= 0.067). Western blot analysis showed a 55% reduction in procollagen I aminopropeptide in perilesional skin treated with corticosteroid alone, as compared with a 45% reduction in corticosteroid/tretinoin-treated perilesional skin. These data indicate that the addition of tretinoin does not impair the efficacy of a topical corticosteroid, in the treatment of psoriasis, and partially ameliorates epidermal atrophy produced by the topical corticosteroid.

Notes: Human epidermal melanocytes were examined for proliferation nuclei' various conditions in the presence or absence of all-trans retinoic acid (RA). Under conditions which supported proliferation, RA at concentrations of 0.25–1.0 μg/ml inhibited cell growth bill was not cytotoxic. When melanocytes were cultured under conditions which by themselves did 1101 support growth, RA did not overcome the growth limitation. Treatment of melanocytes with RA altered their morphological appearance. Alterations included retraction of dendritic processes, increased flattening, and a slight darkening of the cytoplasm in some of the cells. However, when examined biochemically, there was no significant change in the amount of malanin per cell or in lyrosinase activity. RA also inhibited proliferation of six different malignant melanoma lines. Inhibition was observed over the same RA concentrations and over the same time course in the melanoma cells as was seen in melanocytes. Inhibition of melanocytic and melanoma cell proliferation was slowly reversed following removal of RA from the culture medium. These results indicate that RA can inhibit proliferation of melanocytic cells.

Notes: [Auszug] Nature Med. 5, 418– 422 (1999). On page 421, Fig. 4c was labeled incorrectly. The corrected figure is shown to the right. ... We regret this ...

Notes: The family of protein kinase C (PKC) isoenzymes plays a fundamental part in signal transduction, and thereby regulates important cellular functions, including growth, differentiation, cytokine production and adhesion molecule expression. In lesional psoriatic skin. Ca2+-dependent PKC activity, PKC-β protein and epidermal Langerhans cell (LC) PKC-β immunostaining are significantly decreased, indicating activation and subsequent down-regulation of PKC. Whether these changes occur in other inflammatory/hyperplastic dermatoses is, however, unknown. We examined PKC-α and PKC-β expression in normal skin, psoriasis, cutaneous T-cell lymphoma (CTCL), lamellar ichthyosis, non-bullous ichthyosiform erythroderma, atopic dermatitis, urushiol-induced allergic contact dermatitis, and sodium lauryl sulphate (SLS)-induced irritant contact dermatitis. Cryostat sections were stained for PKC-α and PKC-β, and the LC marker CDla, using an immunoperoxidase technique and specific monoclonal antibodies.Double-labelling studies, in normal skin, revealed co-expression of PKC-β and CDla by epidermal LCs. Analysis of the number of PKC-β+ and CDla+ epidermal LCs, in diseased compared with normal skin, revealed three categories: (i) in psoriasis and CTCL. the PKC-β+ epidermal LC number was significantly reduced, whereas the CDla+ epidermal LC number was unchanged; (ii) in allergic and irritant contact dermatitis, both PKC-β+ and CDla+ epidermal LCs were significantly reduced in number; and (iii) in atopic dermatitis, the PKC-β+ epidermal LC number was normal, and CDla+ epidermal LCs were significantly increased in number. Moreover, the ratio of epidermal LC PKC+/CDla+ was reduced in all the dermatoses studied, suggesting activation of PKC-β, with subsequent down-regulation. Within the dermis, increased PKC-β staining of infiltrating cells was observed in all the conditions studied except lamellar ichthyosis and non-bullous ichthyosiform erythroderma. These data indicate that: (i) down-regulation of LC FKC-β occurs in a variety of inflammatory and hyperplastic skin disorders, and is not unique to psoriasis, and (iii the pattern of epidermal LC PKC-β and CDla expression varies among the diseases studied. In mice, PKC activation induces LC migration. Thus, down-regulation of epidermal LC PKC-β associated with reduced CDla+ epidermal LCs in allergic and irritant contact dermatitis suggests that PK.C-β may transduce the signal for migration of LCs from human epidermis.

Notes: The ability of topically applied retinoic acid to improve photoaged skin has stimulated research interest into its mechanism of action. Currently available assay systems are either in-vitro or mouse models, neither of which are truly representative of the in-vivo situation in man. Another drawback is that skin biopsies available from studies using retinoic acid to treat photoageing are of insufficient size to accomplish biochemical and molecular assays. In order to address these problems, a 4-day in-vivo retinoid assay has been developed which serves as a good predictive model for the chronic effects of retinoic acid on skin and helps to characterize the mechanism of action of retinoic acid.

Notes: There is growing evidence that keratinocytc (KC) intercellular adhesion molecule-i (ICAM-i) expression is involved in the epidermal trafficking øf T lymphocytes. To further characterize the molecular basis of KC ICAM-i expression, the detailed kinetics of induction by gamma interferon (IFN-γ)) as well as the phorbol ester, 12-O tetradecanoylphorbol-13-acetate (TPA), were studied. This study reports that KCs express both the class II major histocompatibility antigen (HLA-DR) and ICAM-i in response to IFN-γ, although the response is distinctive for each molecule. Also, TPA induces ICAM-i, but not HLA-DR expression, whilst the protein kinase inhibitor, H7, blocks the TPA, but not the IFN-γ-mediated response. The results provide a molecular basis whereby non-cytokine-mediated stimuli (e.g. TPA) alter KC signal transduction events involving protein kinase-C (PK-C) and thereby generate such immunologically relevant events as ICAM-i expression. Thus, KCs may be targets for both T-cell derived cytokines (e.g. IFN-γ), and non-cytokine TPA-like molecules which stimulate PK-C. Induction of ICAM-i by either mechanism would be capable of instigating intraepidermal T-cell trafficking.

Notes: Since its discovery in 1972, cyclosporin A (CyA) has been widely used in the experimental treatment of multiple inflammatory diseases considered to be of immune-mediated aetiology. In dermatology, oral CyA is most effective in the treatment of psoriasis and has been used successfully for plaque-type, pustular and erythrodermic forms of the disease. While dosages ranging from 1 to 14 mg/kg/day have been used, a starting dose of 4 mg/kg/day gives a rapid response with few side-effects. Nephrotoxicity remains the greatest concern in long-term use of the drug. Although intralesional CyA has proven effective in psoriasis, topical preparations have not. It is hoped that future research will provide effective topical formulations of CyA which are efficacious without the risks inherent in systemic administration.

Notes: With indirect immunofluorescence techniques we demonstrated that recombinant gamma-interferon induced the expression of the class II antigens HLA-DR and HLA-DQ as well as intercellular adhesion molecule-1 (ICAM-1) on normal, cultured human keratinocytes grown in low-calcium, serum-free medium. Each antigen displayed a distinctive cellular staining pattern. HLA-DR was strongly localized to perinuclear zones with intense cell surface expression; HLA-DQ displayed a perinuclear accentuation, but with minimal cell surface staining, and ICAM-1 was strongly expressed in a diffuse cytoplasmic pattern with intense cell surface expression. Keratinocytes grown in medium supplemented with 10% fetal calf serum underwent differentiation, with a diminished expression of all three antigens as compared to those grown in low-calcium, serum-free medium.These results confirm that gamma interferon can differentially regulate HLA-DR nd HLA-DQ expression; that there are probably different biochemical metabolic pathways by which these three molecules are expressed on keratinocytes, and that the expression is also a function of the degree of keratinocyte differentiation. The strong cell surface expression of ICAM-1 is suggested to be of major importance as the recognition molecule, by which T cells bind to gamma interferon exposed keratinocytes, and suggests and integral role for this molecule in epidermal lymphocyte trafficking.