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)

Pentoxifylline (PTX) is a methylxanthine derivative used in a wide range of dermatoses. As well as its hemorrheologic activity, PTX has anti-inflammatory properties. Buflomedil chlorhydrate (BC) is another hemorrheological drug with peripheral vasodilatory action, whose clinical uses are similar to those of PTX. Both drugs increase intracellular levels of cAMP, either secondary to phosphodiesterase inhibition (PTX) or adenyl-cyclase stimulation (BC). Long-term cultures of normal human keratinocytes were prepared in a free-serum medium, and stimulated with 1 mg/ml of phorbol 12-myristate 13-acetate (TPA) and PTX or BC (100-1000 micrograms/ml). Levels of TNF-alpha, IL-1 alpha, IL-1 beta, IL-8 and TGF-beta 1 using ELISA and Northern blot or RT-PCR techniques were measured. TPA-induced TNF-alpha and IL-8 release from keratinocytes. TPA did not induce IL-1 alpha or IL-1 beta release of keratinocytes. TPA increased RNA expression of the TNF-alpha, IL-1 alpha, IL-1 beta, IL-8 and TGF-beta 1. BC diminished TPA-induced TNF-alpha and IL-8 release from keratinocytes; in the case of IL-8 it is possible that this inhibition occur to transcriptional level. Moreover PTX was unable to inhibit TNF-alpha and IL-8 synthesis and expression. PTX and BC reduced TPA-induced IL-1 alpha and beta expression. It is possible that BC action is specifically exerted on keratinocytes, because we did not find similar results with TNF-alpha and IL-8 synthesis in mononuclear peripheral blood cells.
Exp Dermatol 1997 Aug
PMID:Differential modulation of IL-8 and TNF-alpha expression in human keratinocytes by buflomedil chlorhydrate and pentoxifylline. 929 91

The subject of allergic causation of atopic dermatitis (AD) has been a source of controversy for over sixty years. While there is general agreement of allergen-induced asthma and allergic rhinoconjunctivitis, AD lesions cannot be readily or consistently induced by foods and inhalants. The most consistent perturbators of atopic conditions are irritants, probably reflecting the consistent inflammatory cell hyper-reactivity due to elevated cyclic AMP-phosphodiesterase activity. The immunologic reactions are another manifestation of that general cellular dysregulation.
J Dermatol 1997 Aug
PMID:Critical evaluation of food and mite allergy in the management of atopic dermatitis. 930 Nov 42

Cyclic AMP phosphodiesterase (PDE) type 4 has been the subject of considerable interest as a potential molecular target for treating cutaneous inflammatory and allergic disorders; however, little is known regarding the expression of PDE 4 isogenes in human keratinocytes, the predominant cell type present in the epidermis. In this study, we investigated the expression of PDE 4 subtypes in epidermal cells (primary keratinocytes derived from breast skin, epidermoid cell lines A431, KB, and HaCaT) using reverse transcriptase polymerase chain reaction. Analysis of the amplified cDNA showed that there were differences in the expression of PDE 4 isogenes in the epidermal cells. Constitutive expression of the PDE 4 isozymes was detected in untreated epidermal cells at different levels. Transcripts for PDE 4B and 4D were abundantly expressed in breast skin-derived keratinocytes, whereas transcripts for PDE 4A, 4C, and 4D were present in HaCaT cells and transcripts for all the PDE 4 isotypes were present in A431 and KB. PDE 4A and 4C were detectable in HaCaT cells in equal amounts, but PDE 4C was only marginally expressed in the other cells. Of the four isogenes, PDE 4D was abundantly expressed in all the cells. Elevation of intracellular levels of cAMP by forskolin increased the expression of all the hPDE 4 isogenes 2-3-fold as revealed by semiquantitative reverse transcriptase polymerase chain reaction. Western blot analysis of extracts from control and forskolin or dibutyryl cAMP-treated A431 and KB cells demonstrated the presence of proteins with a molecular mass identical to that corresponding to recombinant human PDE 4B. Together, these findings show that PDE 4 isogenes are expressed in keratinocytes to a different degree and that their expression can be modulated by intracellular levels of cAMP.
J Invest Dermatol 1998 Mar
PMID:Cyclic nucleotide phosphodiesterase 4 subtypes are differentially expressed by primary keratinocytes and human epidermoid cell lines. 950 51

We determined the cyclic adenosine monophosphate phosphodiesterase (cAMP-PDE) activity in peripheral blood mononuclear leucocytes from 100 patients with atopic dermatitis (AD) aged 13-57 years (mean +/- SD, 29.8 +/- 17.7 years). The correlation between cAMP-PDE activity and clinical parameters such as the severity of eczema and a personal or family predisposition to atopic respiratory diseases (ARD) (asthma or allergic rhinitis) was examined. Although the enzymic activity varied from normal to very high in the AD patients, cAMP-PDE activity was significantly (P < 0.005) elevated in AD patients (42.1 +/- 22.0 units) as compared with the normal controls (12.4 +/- 5.6) and clinical control subjects (13.4 +/- 9.5). In contrast, we found no correlation between cAMP-PDE activity and the severity of eczema when AD patients were classified into four categories (remission, mild, moderate and severe) according to the extent of their skin involvement. Furthermore, we found that systemic corticosteroid therapy in severe AD patients did not alter the cAMP-PDE activity. cAMP-PDE activity was significantly (P < 0.01) higher in those AD patients who had a personal history of ARD (47.2 +/- 11.2) than in AD patients with a family history of ARD (37.2 +/- 17.4) and those without a personal or family history ('pure' AD) (34.4 +/- 19.8). Nevertheless, the cAMP-PDE activity was significantly higher even in 'pure' AD patients than in the controls. These results suggest that an elevation of cAMP-PDE activity is closely related to a predisposition to respiratory atopy, and does not follow inflammation in AD patients.
Br J Dermatol 1998 May
PMID:Cyclic adenosine monophosphate phosphodiesterase activity in peripheral blood mononuclear leucocytes from patients with atopic dermatitis: correlation with respiratory atopy. 966 32

The immunologic and pharmacophysiologic features of atopic dermatitis have stimulated research seeking to identify relevant effector cells and mediators that characterize chronic skin inflammation. The theory that unifies the various abnormalities associated with atopic dermatitis suggests that hematopoietic cells carrying abnormal genetic expressions of atopy cause clinical disease once they infiltrate the skin and mucosa. The proposed underlying mechanism may be either abnormalities in cyclic nucleotide regulation of marrow-derived cells or allergenic overstimulation that causes secondary abnormalities. The primacy of one mechanism over the other remains unresolved, but this does not obviate their value in identifying two novel therapeutic targets: phosphodiesterase inhibition and immune-intervention alternatives to corticosteroids. New type IV phosphodiesterase inhibitors are proving promising in topical formulations, as are inhibitors of calcineurin, such as FK506 and SDZ ASM 981, an ascomycin macrolactam derivative that in early clinical research appears to offer the potency of a corticosteroid without its adverse side effects. The promising clinical trial profiles of these new topical agents may result in alternative therapies providing potent anti-inflammatory activity without the adverse effects that limit corticosteroid use.
J Am Acad Dermatol 1999 Jul
PMID:Biochemical and immunologic mechanisms in atopic dermatitis: new targets for emerging therapies. 1041 15

The cutaneous lymphocyte-associated antigen defines T lymphocytes with cutaneous tropism under inflammatory conditions. Bacterial infections participate in cutaneous inflammations, such as atopic dermatitis or psoriasis. Bacterial superantigens, such as staphylococcal enterotoxin B, can activate peripheral blood mononuclear cells to induce effector T cells bearing the T cell skin homing receptor cutaneous lymphocyte-associated antigen via enhancement of interleukin-12 production. We have identified and characterized the anti-inflammatory effects of different phosphodiesterase inhibitors on this system. Our data indicate that the selective type 4 phosphodiesterase inhibitor rolipram inhibits the Staphylococcal enterotoxin B-mediated generation of cutaneous lymphocyte-associated antigen positive CD3+ cells from peripheral blood mononuclear cells by reducing interleukin-12 production in a concentration-dependent manner. Conversely, type 3 phosphodiesterase or type 5 phosphodiesterase selective inhibitors were not effective. The rolipram inhibitory effect was on interleukin-12 production, as exogenously added interleukin-12 could revert rolipram suppression. These results suggest that selective type 4 phosphodiesterase inhibition may have beneficial effects on T cell mediated skin inflammatory processes characterized by the presence of bacterial infections, that are thought to exacerbate ongoing skin inflammation.
J Invest Dermatol 1999 Jul
PMID:Rolipram inhibits staphylococcal enterotoxin B-mediated induction of the human skin-homing receptor on T lymphocytes. 1041 23

Optimal treatment of patients with atopic dermatitis requires the knowledge of its pathogenetic factors and the often time-consuming attention to the course of the disease in each individual patient. In the therapeutic attempt, altered skin barrier function, possible provocation factors and psychological matters have to be taken into account. Basic therapy should comprise optimal skin care and the strict avoidance of triggering factors if possible. During periods of acute exacerbation, topical glucocorticosteroids in combination with classic antihistamines with sedative effects are still the drugs of first choice and will result in the rapid relief of symptoms in most patients. UVA1 phototherapy has proven to be a glucocorticoid-equivalent alternative therapy for exacerbated atopic dermatitis. If superinfection with Staphylococcus aureus is evident, topical antiseptics are useful in treating localized lesions, while a general superinfected eczema should be treated with systemic staphylococcal-effective antibacterials. Cyclosporin or extracorporeal photochemotherapy are reserved for patients with very severe atopic dermatitis that is unresponsive to conventional treatment protocols. Promising future therapeutic approaches consist of an improvement in the antipruritic treatment options, the topical application of immunomodifying treatment modalities or phosphodiesterase inhibitors, and possibly Chinese herbal therapies and psychological intervention strategies.
Am J Clin Dermatol
PMID:Optimal management of atopic dermatitis. 1170 4

An increase in phosphodiesterase 4 (PDE4) in blood mononuclear white cells of patients with atopic dermatitis (AD) has been described. This and other skin disorders worsen during stress, during which there are increased circulating levels of adrenaline and glucocorticoids. The aim of this study was to analyse the effect of both these hormones on PDE4 in inflammatory cells. The human monocyte cell line U-937 was used as a model of blood mononuclear leucocytes. For this purpose, (1) the effect of adrenaline on PDE4 activity was determined, (2) the receptor mediating adrenaline actions was characterized, (3) the role of intracellular cAMP in PDE4 activation was investigated and (4) the effect of glucocorticoids on PDE4 activity was also ascertained. Adrenaline at a concentration of 1 micro M produced a two- to threefold selective increase in PDE4 activity in U-937 cells after 4 h of incubation with the hormone. This stimulation was reversible, as well as concentration- and time-dependent. Cycloheximide (10 micro M) induced a blockade of adrenaline-induced stimulation of PDE4. The stimulatory effect was inhibited by propranolol, but not by atenolol or phentolamine, in a concentration-dependent manner and was mimicked by salbutamol. The stimulation of PDE4 was paralleled by an increase in intracellular levels of cAMP. 8-Br-cAMP and forskolin also increased PDE4 activity. After 4 h of incubation in the presence of adrenaline, inhibition of cAMP degradation by rolipram further increased cAMP levels by about 300% and also enhanced PDE4 activity. These results suggest that adrenaline-induced stimulation of PDE4 is mediated by the beta(2)-adrenoceptor and is related to intracellular levels of cAMP, which might trigger expression and synthesis of the enzyme. The synthetic glucocorticoid dexamethasone (in the concentration range 10(-8) to 10(-6) M) showed no effect on PDE4 activity or on the cAMP accumulation induced by adrenaline, even after prolonged (24 h) incubation with the cells. Of the two stress hormones assayed, PDE4 activity was shown to be sensitive to adrenaline elevation but resistant to changes in glucocorticoid levels in the U-937 monocytic cell line.
Arch Dermatol Res 2002 Jul
PMID:Effect of adrenaline and glucocorticoids on monocyte cAMP-specific phosphodiesterase (PDE4) in a monocytic cell line. 1211 50

This paper reviews the theories of the pathogenesis of atopic dermatitis (AD), with a particular emphasis on its immunopathogenesis. The contribution of predisposing factors, immunopathogenic factors and provoking factors in the pathogenesis of AD are considered. Predisposing factors explored in this article include genetics and the disturbance of skin function. Immunopathogenic factors reviewed include T cell dysfunction, biphasic cytokine expression and the role of immunoglobulin E. Provoking factors considered include microbial factors, psychosomatic interactions, contact allergens and irritants, inhalant allergens, food and climate. Immunosuppressive treatments reviewed include cyclosporin, azathioprine, methotrexate, tacrolimus, interferon-gamma, phosphodiesterase inhibitors and pimecrolimus (SDZ ASM 981).
Australas J Dermatol 2002 Nov
PMID:Atopic dermatitis: review of immunopathogenesis and advances in immunosuppressive therapy. 1242 30

Phosphodiesterase inhibitors possess anti-inflammatory and immunomodulatory properties and seem to have a great potential in the treatment of inflammatory skin diseases; however, an overall study on the effects of specific phosphodiesterase inhibitors, such as rolipram on the processes involved in the extravasation of lymphoid cells has not been performed. In this work we have assessed the effect of rolipram on the adhesion, polarization, and migration of normal human T lymphocytes. We found that low concentrations of rolipram were able to inhibit significantly the adhesion of T cells to the beta1 and beta2 integrin ligands vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. Rolipram also interfered with the activation of integrins, and significantly inhibited the homotypic aggregation of T lymphocytes induced by anti-beta1 and anti-alpha4 integrin chain monoclonal antibodies. In addition, rolipram had a downregulatory effect on the activation of T cells, and significantly diminished the expression of the activation antigens CD69, CD25, and CD98 induced by phytohemagglutinin. Finally, this drug inhibited the polarization and transendothelial migration of T lymphocytes induced by the chemokine CXCL12 (SDF-1) and the chemotactic cytokine interleukin-15. The results indicate that rolipram, at low concentrations, exerts an important anti-inflammatory and immunomodulatory effect, and suggest that this selective phosphodiesterase inhibitor may be an effective tool for the therapy of immune-mediated diseases.
J Invest Dermatol 2003 Jul
PMID:Rolipram inhibits polarization and migration of human T lymphocytes. 1283 67


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