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)

The effects of cAMP-elevating agents on antigen-induced IL-5 (interleukin-5) messenger RNA expression and protein production were examined in vitro in an antigen-driven system of splenocytes from ovalbumin sensitized BALB/c mice. IL-5 production was inhibited by rolipram, a type 4 phosphodiesterase (PDE4) inhibitor, dose-dependently (maximally at 10(-5) M) and by dibutyryl-cAMP (db-cAMP) (3 x 10(-4) M), but not by the type 3 and type 5 PDE inhibitors milrinone and zaprinast (10(-5) M), respectively. Forskolin (10(-5) M), an adenylate cyclase activator, was noninhibitory alone but potentiated inhibition by rolipram. Inhibition was associated with a decrease in IL-5 mRNA expression. Cycloheximide 10(-6) M and actinomycin 2 micrograms/ml abolished IL-5 production and mRNA expression. We conclude that in splenocytes from sensitized mice, IL-5 production and mRNA expression depend on antigen stimulation. The time course of IL-5 protein production is closely related to IL-5 mRNA expression and depends on de novo protein synthesis. db-cAMP and a selective PDE4 inhibitor, alone or in combination with forskolin, are the only cAMP-elevating agents that dose-dependently inhibited antigen-induced IL-5 mRNA expression and protein production. These results are in agreement with in vivo inhibition by a selective PDE4 inhibitor of antigen-induced pulmonary eosinophil infiltration and IL-5 production in sensitized mice, and they suggest that PDE4 inhibitors have potential for treating respiratory allergy.
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PMID:In vitro down-regulation of antigen-induced IL-5 gene expression and protein production by cAMP-specific phosphodiesterase type 4 inhibitor. 881 36

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.
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PMID:Effect of adrenaline and glucocorticoids on monocyte cAMP-specific phosphodiesterase (PDE4) in a monocytic cell line. 1211 50

Paired Y-organs secrete ecdysteroid hormones that control cycles of growth and molting in crustaceans. Y-Organs are regulated, at least in part, by molt-inhibiting hormone (MIH), a polypeptide produced and released by the X-organ/sinus gland complex of the eyestalks. In the present studies, crab (Callinectes sapidus) Y-organs were incubated in vitro in the presence of [(35)S]methionine, and cyclic nucleotide analogs or experimental agents that influence the cAMP signaling pathway. In 4-hr incubations, 8-Br-cAMP and db-cAMP (but not 8-Br-cGMP) suppressed incorporation of [(35)S]methionine into Y-organ proteins; the effect of 8-Br-cAMP was concentration-dependent. Autoradiograms of radiolabeled Y-organ proteins separated on SDS-PAGE gels indicated the effect of 8-Br-cAMP was general (as opposed to selective) suppression of protein synthesis. Addition of both forskolin (an adenylyl cyclase activator) and 3-isobutyl-1-methylxanthine (a phosphodiesterase inhibitor) likewise suppressed incorporation of [(35)S]methionine into Y-organ proteins. Cycloheximide (a protein synthesis inhibitor) suppressed incorporation of [(35)S]methionine into Y-organ proteins and secretion of ecdysteroids. The combined results suggest that cAMP is involved in regulation of protein synthesis in C. sapidus Y-organs. We are currently investigating the link of protein synthesis to ecdysteroid production, and the possibility of cross-talk between cAMP and other cellular signaling pathways in Y-organs.
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PMID:Regulation of protein synthesis in Y-organs of the blue crab (Callinectes sapidus): involvement of cyclic AMP. 1649 43


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