Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The functional activity of lymphocyte function-associated antigen 1 (LFA-1) on leukocytes can be regulated by T-cell receptor (TCR) stimulation and pharmacologic agents. It was of interest to determine if functionally active LFA-1 could be reconstituted on a nonhematopoietic, LFA-1-negative cell line. We report the expression of LFA-1 and diethylaminoethyl (DEAE) Mac-1 alpha beta heterodimers on the cell surface of a fibroblastoid cell line, COS, by DEAE dextran cotransfection of the alpha and beta subunit cDNAs. Immunoprecipitation studies demonstrated that the alpha and beta subunit was expressed in heterodimers. The alpha or beta subunit was expressed at lower levels after transfection with the alpha or beta subunit cDNA alone. Cotransfection of the alpha and beta subunit cDNAs, but not transfection of alpha or beta alone, was sufficient to reconstitute intercellular adhesion molecule-1 (ICAM-1) binding activity. Consistent with this observation, LFA-1 on the fibroblastoid cells possesses the activation epitope defined by the L16 monoclonal antibody (mAb). This epitope marks the conversion of LFA-1 from the low to high avidity state on peripheral blood T lymphocytes (PBLs) and is constitutively present on activated cell lines. In contrast to LFA-1 on leukocytes, the functional activity of LFA-1 on fibroblastoid cells was not influenced by phorbol ester treatment. Furthermore, the use of agents that interfere with intracellular signaling, a protein kinase C inhibitor, cAMP analogue, or the combination of a phosphodiesterase inhibitor and adenyl cyclase activator, did not affect the binding of COS cells expressing LFA-1 to purified ICAM-1.
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PMID:The leukocyte integrin LFA-1 reconstituted by cDNA transfection in a nonhematopoietic cell line is functionally active and not transiently regulated. 171 36

We examined the effect of agents which augment intracellular levels of cyclic adenosine monophosphate on the expression of adhesion molecules on human umbilical vein endothelial cells. Surface protein expression of vascular cell adhesion molecule-1, endothelial leukocyte adhesion molecule-1, or intercellular adhesion molecule-1, which is induced by tumor necrosis factor, interleukin-1, and lipopolysaccharide, was not induced by pentoxyfilline, a phosphodiesterase inhibitor, nor by dibutyryl cyclic adenosine monophosphate. Furthermore, neither of these two cyclic adenosine monophosphate elevating agents nor HA 1004, an inhibitor of the cyclic adenosine monophosphate-dependent protein kinase, had any effect on tumor necrosis factor-alpha-induced surface expression of these adhesion molecules. Likewise, cyclic adenosine monophosphate elevating agents were without effect on leukocyte adherence to endothelium stimulated either with these agents alone or in combination with tumor necrosis factor-alpha. Additionally, activators of the stimulatory or inhibitory guanine nucleotide-dependent binding proteins did not affect TNF-alpha-induced surface expression of endothelial leukocyte adhesion molecule-1 or vascular cell adhesion molecule-1.
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PMID:Cytokine-induced adhesion molecule expression on human umbilical vein endothelial cells is not regulated by cyclic adenosine monophosphate accumulation. 839 31

The outcome of immune responses can be predicted by the lymphokine production pattern of the participating cells. Cytokines of the T helper type 1 (Th1) cells mediate inflammatory responses and delayed-type hypersensitivity (DTH), whereas Th2-like T cells predominantly produce cytokines, which stimulate antibody production by B cells. Immunoregulatory therapy of autoimmune diseases with unknown antigens may be achieved by inhibiting the production of inflammatory cytokines and induction of protective cytokines of Th2-like T cells. To determine the immunoregulatory capacity of the phosphodiesterase inhibitor pentoxifylline (PTX), which is known to suppress the production of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), this drug was used in mitogen and antigen-stimulated lymphocyte cultures as well as in patients with multiple sclerosis. PTX significantly decreased TNF-alpha and interleukin-12 (IL-12), whereas it increased IL-4 and IL-10 production. In addition, PTX inhibited cell proliferation, which was associated with a marked reduction in CD25 (IL-2 receptor alpha-chain) and CD54 (intercellular adhesion molecule-1; ICAM-1) expression. Increasing doses of PTX significantly reduced TNF-alpha and IL-12 mRNA expression of blood mononuclear cells, but increased IL-4 and IL-10 expression in eight patients with relapsing-remitting multiple sclerosis. These results indicate that PTX modulates immune reactions favouring a Th2-like response and may therefore be useful for the treatment of autoimmune diseases with a dominant Th1-like T cell response.
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PMID:Pentoxifylline, a phosphodiesterase inhibitor, induces immune deviation in patients with multiple sclerosis. 863 62

Bronchial epithelial cells express the intercellular adhesion molecule-1 that mediates binding of activated neutrophils via interaction with Mac-1 and/or leukocyte function-associated antigen-1. In this study, we examined whether increased intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) affected neutrophil adhesion to the human bronchial epithelial cells. It was found that the N-formylmethionyl-leucyl-phenylalanine (fMLP)-stimulated neutrophil adhesion was concentration dependently inhibited when the cAMP analogs dibutyryl adenosine 3',5'-cyclic monophosphate or 8-bromoadenosine 3',5'-cyclic monophosphate were present. The beta-adrenergic receptor agonists isoprenaline and salmeterol, in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), were also able to inhibit the fMLP-stimulated adhesion of neutrophils to bronchial epithelial cells. These agonists in combination with IBMX significantly increased the intracellular cAMP level in both neutrophils and epithelial cells. Preincubation of neutrophils with the long-acting beta2-adrenergic receptor agonist salmeterol (in the presence of IBMX) inhibited their fMLP-stimulated adhesion to epithelial cells, whereas pretreatment of epithelial cells did not influence the adhesion process. When ethanol-fixed epithelium was used, salmeterol pretreatment also diminished the adhesion of stimulated neutrophils. Moreover, combinations of salmeterol or isoprenaline with IBMX inhibited fMLP-upregulated Mac-1 expression. Therefore, we conclude from these data that elevation of intracellular cAMP in the neutrophil inhibits stimulated neutrophil adhesion to bronchial epithelial cells via Mac-1.
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PMID:Increased cAMP levels in stimulated neutrophils inhibit their adhesion to human bronchial epithelial cells. 914 28

We have examined the effect of elevating cyclic AMP levels on cytokine-mediated enhancement of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) gene expression by astrocytes. Treatment of astrocytes with the cyclic AMP mimetic dibutyryl-cyclic AMP, or the agonists norepinephrine, forskolin, prostaglandin E2, and cholera toxin alone had no effect on ICAM-1 or VCAM-1 mRNA gene expression. However, elevating cyclic AMP levels within the cells by these agents suppressed interleukin-1beta- and tumor necrosis factor-alpha-induced adhesion molecule expression at both the mRNA and protein levels. The phosphodiesterase type IV inhibitor, rolipram, was able to potentiate the inhibitory effect of forskolin on ICAM-1 and VCAM-1 gene expression. Inhibition of tumor necrosis factor-alpha-induced VCAM-1 mRNA levels by forskolin was partially due to enhanced degradation of VCAM-1 message, whereas the decay rates of tumor necrosis factor-alpha-induced ICAM-1 message and interleukin-1beta-induced ICAM-1/VCAM-1 message were not affected by forskolin treatment. These results demonstrate that the pathways used by interleukin-1beta and tumor necrosis factor-alpha to induce adhesion molecule expression are antagonized by cyclic AMP-dependent protein kinase-mediated signaling pathways.
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PMID:Elevation of cyclic AMP levels in astrocytes antagonizes cytokine-induced adhesion molecule expression. 932 72

The effects of pentoxifylline (POX) on macrophage migration and myelin uptake were studied in an in vitro model of myelin phagocytosis. The POX is a phosphodiesterase inhibitor which inhibits TNF-alpha (tumor necrosis factor alpha) production and reduces ICAM-1 (intercellular adhesion molecule-1) expression by macrophages. Both of these molecules have earlier been shown to be involved in the process of myelin recognition and degradation. In the present series of experiments, cocultured peripheral nerves and macrophages were treated with different concentrations of POX. Untreated controls were massively invaded by macrophages which ingested the degenerating myelin sheaths. High concentrations of POX (100 microg ml(-1)) inhibited macrophage invasion of the nerves. Lower POX concentrations (50 microg ml(-1)), in contrast, lead to an increased myelin uptake by phagocytic cells without affecting macrophage migration. These data indicate that POX may regulate different effector functions of macrophages such as migration and myelin phagocytosis during Wallerian degeneration. This is important for inflammatory demyelinating conditions in the central or peripheral nervous system (PNS) in which macrophages are also important effector cells. Since POX is used as an immunomodulatory drug in demyelinating diseases, its effects on the described macrophage functions may be of high relevance. An increased myelin uptake during Wallerian degeneration may also support a more efficient axonal regeneration by removing axonal outgrowth inhibitors.
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PMID:Concentration-dependent effects of pentoxifylline on migration and myelin phagocytosis by macrophages. 972 31

The present study investigated the effect of prostaglandin (PG) E2 and PGI2 on intercellular adhesion molecule-1 (ICAM-1) expression in interleukin-1 beta (IL-1 beta)-stimulated human gingival fibroblasts (HGF). IL-1 beta potently induced ICAM-1 expression in HGF and indomethacin, a cyclooxygenase inhibitor, enhanced ICAM-1 expression in the cells. These data showed that endogenous PGs generated by HGF stimulated with IL-1 beta downregulated ICAM-1 expression. IL-1 beta significantly increased the levels of PGE2 and, to a lesser extent, those of 6-keto-PGF1 alpha (a stable metabolite of PGI2) in the culture media of HGF. Indomethacin completely inhibited the production of PGE2 and 6-keto-PGF1 alpha in IL-1 beta-stimulated HGF. Exogenous PGE2 and carbacyclin (a stable derivative of PGI2) in the presence of indomethacin dose-dependently suppressed ICAM-1 expression in IL-1 beta-challenged HGF. Since PGE2 and PGI2 are known to elevate intracellular cyclic AMP (cAMP) levels, we examined the effect of dibutyryl cAMP, a cAMP analogue, and isobutylmethylxanthine, a phosphodiesterase inhibitor, on ICAM-1 expression. Both agents downregulated ICAM-1 expression in IL-1 beta-stimulated HGF. These results suggest that PGE2 and PGI2 downregulate ICAM-1 expression in IL-1 beta-stimulated HGF through a cAMP-dependent mechanism and that intracellular cAMP elevation in HGF may control inflammatory and immune responses in periodontal disease.
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PMID:Prostaglandin E2 and I2 regulate intercellular adhesion molecule-1 expression in interleukin-1 beta-stimulated human gingival fibroblasts. 1020 38

Pentoxifylline (PX) is a phosphodiesterase inhibitor which effectively increases overall cAMP levels within the cell. This study analyses the ability of PX to alter growth, adhesion and lymphokine activated killer (LAK) cell-mediated lysis of the C8161 and Hs294T human melanoma cell lines, and investigates the role of intercellular adhesion molecule-1 (ICAM-1) in the tumour/LAK cell interaction. We have demonstrated that 4 days' pretreatment with PX (100-250 microg/ml) significantly reduces cell numbers in a dose- and time-dependent manner, with cell numbers decreasing by 67.5% in the C8161 cell line and by 65.4% in the Hs294T cell line with 250 microg/ml PX. Adherence of both cell lines to a range of extracellular matrix components is not affected by PX, with the exception of the C8161 cells, where 4 days' pretreatment with 250 microg/ml PX causes a 24.2% reduction in adherence to fibronectin. Four days' pretreatment of the tumour cells with 250 microg/ml PX leads to increased lysis of the C8161 cells and decreased lysis of the Hs294T cells. The addition of blocking ICAM-1 antibody (10 microg/ml) to the C8161 cells at an effector:tumour cell ratio of 40:1 causes a 2.3-fold reduction in lysis of both control and PX-treated cells. Addition of blocking ICAM-1 antibody (5 microg/ml) to Hs294T cells reduces lysis of control cells 1.8-fold. In PX-treated Hs294T cells, 10 microg/ml of blocking ICAM-1 antibody significantly reduces lysis 1.5-fold. The more aggressive C8161 cells produce 5-fold greater levels of soluble ICAM-1 (sICAM-1) than the poorly metastatic Hs294T cells. PX (10-250 microg/ml) causes a dose-dependent increase in sICAM-1 expression in both cell lines, with maximum increases of 4.7-fold and 4.3-fold in the Hs294T and C8161 cell lines, respectively, following 4 days' pretreatment with 250 microg/ml PX. Collectively, these data demonstrate the ability of PX to alter tumour cell growth, adhesion and LAK cell-mediated lysis and also support a role for the involvement of ICAM-1 in the tumour/LAK cell interaction.
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PMID:Pentoxifylline-induced modulation of melanoma cell growth, adhesion and lymphokine activated killer cell-mediated lysis. 1033 32

Type IV phosphodiesterase inhibitors are able to suppress EAE. To investigate the effects of this therapy in the central nervous system, we serially analyzed from days 7 to 17 postinoculation the gene expression pattern of tumor necrosis factor (TNF), lymphotoxin, interferon-gamma, interleukin-1beta, the inducible nitric oxide synthase (iNOs), interleukin-10, the vascular cell adhesion molecule-1 (VCAM-1) and the intercellular adhesion molecule-1 (ICAM-1) in the spinal cord of Lewis rats with actively induced EAE, treated with Rolipram. Treated rats had a delayed and milder disease, and reduced numbers of infiltrates in the nervous tissue. The gene expression profile was similar to that of untreated rats, although delayed, with no evidence of IL-10 upregulation during the observation period. The delayed inflammation was not associated with changes in the expression of VCAM-1 and ICAM-1. In peripheral blood mononuclear cells, TNF mRNA levels were decreased and interleukin-10 was unchanged. This therapy did not alter the proliferative ability of T lymphocytes against myelin basic protein. The encephalitogenic potential of splenocytes from treated animals was also unaffected. The high levels of both iNOs mRNA and nitric oxide (NO) found before the appearance of clinical signs, suggests that NO generation might be a contributing factor to the therapeutic benefit achieved by Rolipram in the rat.
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PMID:Type IV phosphodiesterase inhibition in experimental allergic encephalomyelitis of Lewis rats: sequential gene expression analysis of cytokines, adhesion molecules and the inducible nitric oxide synthase. 1038 42

1. Rolipram, a selective phosphodiesterase (PDE) type 4 inhibitor, was used to characterize leukocyte recruitment mechanisms in models of acute and subacute inflammation. Intravital microscopy within the rat mesenteric microcirculation was employed. 2. Mesentery superfusion with PAF (0.1 microM) induced a significant increase in leukocyte rolling flux, adhesion and emigration at 60 min. Rolipram pretreatment, markedly inhibited these parameters by 100, 95 and 95% respectively. 3. Similar effects were observed when the mesentery was superfused with LPS (1 microg ml(-1)) for the same time period and these leukocyte parameters were nearly abrogated by rolipram pretreatment. 4. LPS exposure of the mesentery for 4 h caused a greater increase in leukocyte rolling flux, adhesion and emigration which were inhibited by rolipram administration by 51, 71 and 81% respectively. 5. Immunohistochemistry revealed a significant increase in P-selectin expression after 60 min superfusion with PAF which was attenuated by rolipram. 6. LPS exposure of the mesentery for 4 h caused a significant increase in P- and E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression. Rolipram pretreatment down-regulated both P- and E-selectin expression but had no effect on ICAM-1 and VCAM-1 expression. 7. Significant increases in plasma cyclic AMP levels were detected at 4.5 h after rolipram administration. 8. In conclusion, we have demonstrated that rolipram is a potent in vivo inhibitor of leukocyte-endothelial cell interactions. The effects observed are mediated through endothelial P- and E-selectin downregulation. Therefore, selective PDE-4 inhibitors may be useful in the control of different inflammatory disorders.
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PMID:Rolipram inhibits leukocyte-endothelial cell interactions in vivo through P- and E-selectin downregulation. 1195 89


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