Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atopic dermatitis is a genetically determined inflammatory condition in which the primary defect is expressed in one or more hematopoietic cells that infiltrate the skin. It is a multifactorial disease with inflammation triggered by a variety of factors. Among these, atopic dermatitis has been experimentally induced and reproduced by emotional-stress interviews and food challenges only. The inflammatory events of atopic dermatitis appear to initiated by mast cells, but eosinophils, monocytes, and T lymphocytes (predominantly CD4) also are present in lesions. The secondary effects of inflammation are a dry, brittle stratum corneum and pruritus, causing excoriation and a lichenified epidermal layer resulting from chronic rubbing. Therapeutic approaches to atopic dermatitis may be directed at several points in the evolution of the disease. Agents including emollients are needed to preserve and restore the stratum corneum barrier, and effective antipruritics are required to reduce the self-inflicted damage to the involved skin. Various other agents may be needed to antagonize mediators or cytokines and to inhibit cytokine expression and release from lesional, immune-effector cells. Likewise, new phosphodiesterase inhibitors, calcium-active agents, and antiallergic drugs may be used to reduce the quantity and pathologic functioning of inflammatory infiltrating cells in the skin.
J Am Acad Dermatol 1991 Jun
PMID:Atopic dermatitis: new therapeutic considerations. 167 14

Epidermal cells from psoriatic lesions demonstrate a very low cAMP response to beta-adrenergic stimuli. We have shown that a similar abnormality occurs in dermal fibroblasts from affected areas of skin. The cells, after 5-12 passages in tissue culture, had a much reduced response to 10(-8) M and 10(-6) M isoproterenol when compared with fibroblasts from control subjects. The abnormality was not abolished by the addition of the phosphodiesterase inhibitor, 3-isobutyl-I-methylxanthine. Other putative agonists tested were vasoactive intestinal peptide and peptide histidine methionine. Neither of these had an effect on dermal fibroblasts from either normal controls or from lesions of psoriasis.
Br J Dermatol 1990 Apr
PMID:Beta-adrenergic stimulation of cyclic AMP is defective in cultured dermal fibroblasts of psoriatic subjects. 169 75

Elevated activity of cyclic adenosine monophosphate-specific phosphodiesterase (PDE) has been previously documented in the peripheral blood mononuclear leucocytes (MNLs) of patients with atopic dermatitis (AD). Because of the potential interactions of the cyclic nucleotide and inositol secondary messenger systems we sought to determine whether differences exist in the inositol uptake and metabolism between atopic and normal MNLs. We found no difference in the uptake of tritiated inositol by MNL between 19 atopic patients and 16 non-atopic control subjects. However, after stimulation of MNLs by concanavalin A, there was a significantly greater metabolism of inositol to inositol-1-phosphate (IP1) in the controls compared to the atopic MNLs; the mean percentage rise in the IP1 fraction over baseline level was 40% in the atopics, but almost 200% in controls after 2 h. Diminished inositol metabolism in atopic MNLs may explain the reduced cell-mediated immunity that characterizes the atopic state.
Br J Dermatol 1991 Feb
PMID:Inositol metabolism in mononuclear leucocytes from patients with atopic dermatitis. 184 40

Atopic dermatitis and the other atopic conditions occur as a result of direct or indirect influences from cells of hematopoietic origin. Cellular immune abnormalities have been described, but appear to be secondary to cutaneous inflammation in atopic dermatitis. Pharmacophysiologic abnormalities are numerous and may relate to defective cyclic nucleotide metabolism in circulating and infiltrating leukocytes. A consistent leukocyte abnormality is elevated cyclic AMP-phosphodiesterase. This enzyme abnormality results in reduced intracellular cyclic AMP, creating a net permissive effect upon cell function. Phosphodiesterase inhibitors have been demonstrated to reduce abnormal histamine release and IgE production by cultured leukocytes. Studies of phosphodiesterase and associated defects in atopic leukocytes may lead to delineation of basic pathogenetic mechanisms as well as providing the potential for therapeutic targeting.
J Dermatol Sci 1990 Jan
PMID:Phosphodiesterase and immune dysfunction in atopic dermatitis. 196 82

The role of melanocyte stimulating hormone (MSH) as a mediator of the melanogenic response to ultraviolet radiation (UVR) was examined in C57 BL/6 mice. While exposure to UVR (250-300 nm) for 7, 14 and 27 days increased tyrosinase activity in epidermal melanocytes of the ear MSH had no effect and failed to alter the response to UVR. Plasma alpha-MSH concentrations were unchanged following UVR. Theophylline, a phosphodiesterase inhibitor, also had no effect on epidermal tyrosinase activity in non-irradiated and UV irradiated mice. Prostaglandin E2 and arachidonic acid were also ineffective in non-irradiated and UV irradiated mice and indomethacin, an inhibitor of prostaglandin synthesis, failed to increase epidermal tyrosinase activity after UVR. On the other hand, 12-0-tetradecanoyl phorbol 13 acetate, an activator of protein kinase C, increased epidermal tyrosinase activity in non-irradiated mice and also enhanced the effect of UVR.
J Dermatol Sci 1990 Jul
PMID:The effect of ultraviolet radiation and melanocyte-stimulating hormone on tyrosinase activity in epidermal melanocytes of the mouse. 212 69

The atopic conditions, atopic dermatitis, asthma, and allergic rhinitis, may arise as a result of infiltrating bone marrow-derived cells into skin or respiratory mucosae. Release of inflammatory factors from these cells could account for cutaneous vascular instability and pruritus in atopic dermatitis. Erythema and itch have been induced by experimental stress interviews and by blind food challenges. In the latter, increased plasma histamine was detected and correlated with cutaneous reactions. Basophils from patients with atopic dermatitis have increased histamine release after exposure to immunologic or nonimmunologic lectin stimuli. This increased releasability may relate to inadequate cyclic AMP regulation of cell function. We have found that leukocytes of patients with atopic dermatitis have elevated phosphodiesterase activity and consequently reduced intracellular cyclic AMP. Exposure of the cells to a phosphodiesterase inhibitor caused considerable reduction in histamine release. Similarly, exposure of atopic B lymphocytes to a phosphodiesterase inhibitor greatly reduced the high spontaneous IgE synthesis in mononuclear leukocyte cultures. Elevated leukocyte phosphodiesterase activity may also serve as a marker for the atopic diathesis. We have found elevated enzyme activity in umbilical cord blood from newborns with atopic parents, suggesting that this defect may relate to a genetically determined defect. These studies have provided insight into basic abnormalities associated with atopic dermatitis and the atopic diathesis. Defects of regulatory mechanisms in immune and inflammatory cells may help explain the seemingly disparate disorders of physiologic, pharmacologic, and immunologic systems in atopy.
J Invest Dermatol 1985 Jul
PMID:Immunopharmacology of the atopic diseases. 240 83

Adenosine-adenylate cyclase response in pig skin epidermis showed a specific increase after long-term (24 h) incubation in the presence of 0.5%-1% dimethyl sulfoxide (DMSO). There was no significant difference between control and DMSO-treated epidermis with regard to cyclic AMP (cAMP) phosphodiesterase activity. DMSO had no effect on the basal cAMP levels of epidermis; beta-adrenergic and histamine-adenylate cyclase responses were not affected. The direct addition of DMSO at the time of incubation with various adenylate cyclase stimulators (adenosine, epinephrine, and histamine) had no effect on agonist-induced cAMP accumulation effects. It was concluded that DMSO affected epidermal keratinocytes during long-term incubation, resulting in a specific increase in the adenosine-adenylate cyclase response. Although the biological significance of this DMSO effect remains to be determined, it should be kept in mind when using DMSO as a solvent for various chemicals in the experiments dealing with epidermal keratinocytes in vitro.
Arch Dermatol Res 1986
PMID:Dimethyl sulfoxide-induced augmentation of adenosine-adenylate cyclase response of pig skin epidermis. 243 59

The adenylate cyclase system of an established human trichilemmoma cell line was investigated. Stimulators of human epidermal adenylate cyclase system, epinephrine, histamine, adenosine, and prostaglandin E increased cyclic AMP levels of the trichilemmoma cells. The effects of epinephrine, histamine, and adenosine were inhibited by the addition of propranolol (a beta-adrenergic antagonist), cimetidine (histamine H2-antagonist), and theophylline (adenosine-receptor antagonist), respectively. The epinephrine, histamine, and prostaglandin E effects were augmented by the addition of cyclic AMP (cAMP) phosphodiesterase inhibitor, isobutylmethylxanthine (IBMX); the adenosine effect was augmented by another phosphodiesterase inhibitor, papaverine. Without the addition of these phosphodiesterase inhibitors, the maximal accumulations were observed at 3 min incubation. Following this, the cAMP content returned to the basal level, and the cells did not respond to repeated stimulations with the same initial stimulator. This fact indicates receptor-specific refractoriness. For example, epinephrine-pretreated cells did not respond to epinephrine, but retained their sensitivity to histamine. It has been known that normal epidermal keratinocytes are regulated in vitro by glucocorticoids, colchicine, and retinoids, resulting in the augmentation of their beta-adrenergic response. Only hydrocortisone treatment on the trichilemmoma cells resulted in the augmentation of the beta-adrenergic response. Although the established human trichilemmoma cell line has similar adenylate cyclase systems as normal epidermis, it apparently has lost some of the regulatory mechanism of the beta-adrenergic response.
Arch Dermatol Res 1987
PMID:Adenylate cyclase system of human trichilemmoma cell line. 244 40

Psoriatic involved epidermis reveals variously altered receptor-adenylate cyclase responses; among them the most prominent is defective beta-adrenergic adenylate cyclase response, which is normally the major receptor-adenylate cyclase system of human epidermis. It is known that activation of hormone-stimulated adenylate cyclase, a membrane-bound enzyme complex, requires functional coupling of at least 3 distinct subunits: 1) receptor subunit (R), 2) guanine nucleotide binding protein (G), and 3) catalytic subunit (C). The precise nature of the beta-adrenergic defect in the psoriatic epidermis, however, remains to be determined, especially in terms of G and C function. Using the involved and uninvolved skin from psoriatic patients, we investigated effects of cholera toxin (which monitors G-C interaction) and forskolin (which monitors C function) on the adenylate cyclase system of epidermis, which were compared with those of normal human epidermis. Both agents increased cyclic AMP levels of involved, uninvolved, and normal human epidermis. Marked accumulations were observed in the presence of cyclic nucleotide phosphodiesterase inhibitor, isobutyl-methylxanthine (IBMX); without the phosphodiesterase inhibitor, the effect of each agent was minimal. Comparison of the effects of cholera toxin revealed that the psoriatic involved epidermis accumulates much more cyclic AMP than the uninvolved epidermis (involved: 193 +/- 65; uninvolved: 117 +/- 54 pmoles/mg protein/5 h). Similarly forskolin-induced cyclic AMP accumulations of the involved epidermis were much more than those of uninvolved epidermis (involved: 374 +/- 152; uninvolved: 101 +/- 41 pmoles/mg protein/2 h). Those of normal human epidermis were not significantly different from those of uninvolved epidermis (cholera toxin: 99 +/- 36 pmoles/mg protein/5 h; forskolin: 84 +/- 22 pmoles/mg protein/2 h). Our results indicate that G and C function and their interaction is not defective (but rather increased) in the psoriatic involved epidermis. This suggests that the defective beta-adrenergic response of psoriatic involved epidermis reflects defective R or R-G interaction of the epidermal adenylate cyclase system.
J Invest Dermatol 1988 Aug
PMID:Increased cholera toxin-, and forskolin-induced cyclic AMP accumulations in psoriatic involved versus uninvolved or normal human epidermis. 245 58

In FRSK cells, a cell line derived from fetal rat epidermal cells, cyclic AMP-elevating agents forskolin (10 microM) and cholera toxin (10 ng/ml) increased cellular cyclic AMP content and suppressed [3H] thymidine incorporation. These effects of forskolin were enhanced by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.1 mM). Dibutyryl cyclic AMP (1 mM), an analog of cyclic AMP, decreased not only basal but also both tumor promoter 12-O-tetradecanoylphorbol-13-acetate- and epidermal growth factor-stimulated [3H] thymidine incorporation. From these results, we suggest that cyclic AMP may be a negative regulatory factor of DNA synthesis in FRSK cells.
J Dermatol 1989 Feb
PMID:Cyclic AMP as a negative regulator of DNA synthesis in FRSK cells, a fetal rat epidermal cell line. 247 Jul 96


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