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)

Tumor necrosis factor (TNF) is a macrophage-derived mediator responsible for many of the pathophysiologic manifestations of endotoxic shock. We now demonstrate that amrinone, a noncatechol inotrope, strongly inhibits lipopolysaccharide (LPS)-induced TNF production at concentrations readily achieved in vivo. This inhibition is apparent in murine macrophages, in macrophage cell lines, in vivo, and in cell lines containing a reporter gene construct that substitutes the chloramphenicol acetyl transferase (CAT) coding sequence for the TNF coding sequence and introns. Inhibition by amrinone (like inhibition by pentoxifylline) is manifested at the level of mRNA accumulation, in contrast to inhibition caused by dexamethasone. Combined application of dexamethasone and amrinone caused additive inhibition of TNF biosynthesis in vitro. Furthermore, treatment of mice with amrinone immediately prior to endotoxin challenge led to significantly improved survival. These findings suggest that amrinone possesses antiinflammatory as well as inotropic properties that may make it an appropriate agent for use in septic shock or other serious bacterial infections. Abrupt removal of amrinone or pentoxifylline from the culture medium prior to LPS stimulation, however, caused significantly augmented TNF production. Therefore, amrinone and other phosphodiesterase inhibitors may also enhance sensitivity to LPS during a period of time following discontinuation of therapy.
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PMID:Effect of amrinone on tumor necrosis factor production in endotoxic shock. 161 5

Tumor necrosis factor (TNF) actions in target tissues are mediated by various signalling pathways. The effect of TNF to stimulate resorption in fetal rat limb bones is not inhibited by indomethacin. The current studies were designed to assess the role of cyclic AMP (cAMP) and calcium as second messengers in this prostaglandin-independent action of TNF on bone resorption. TNF alone failed to increase cyclic AMP in fetal rat limb bones after either brief (15 min) or long-term (72 h) treatment. TNF-stimulated resorption in fetal rat limb bones was enhanced by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). In short term incubations, the combination of TNF + IBMX did not elicit increases in cAMP in the limb bones. In 72 h cultures, addition of IBMX revealed a dose-dependent effect of TNF to increase cAMP. TNF produced a significant increase in inositol phosphate turnover in limb bones, with a greater response at 5 min than at 1 or 20 min. The calcium channel blocker nitrendipine inhibited TNF-stimulated resorption in the fetal rat limb bones. TNF-stimulated resorption was attenuated by pretreatment with pertussis toxin (PTx). PTx did not inhibit the effect of TNF to increase inositol phosphate turnover. TNF did not increase cAMP, intracellular calcium, or inositol phosphates in the UMR-106 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evaluation of the role of second messenger systems in tumor necrosis factor-stimulated resorption of fetal rat limb bones. 751 60

Tumor necrosis factor-alpha (TNF) exerts a wide spectrum of biological activities and contributes to the pathophysiology of septic shock. Elevated circulating levels of TNF have also been reported in patients with severe chronic heart failure. We studied the effect of amrinone, a class III cyclic nucleotide phosphodiesterase inhibitor used in the treatment of acute heart failure, on the synthesis of TNF in vitro. Peripheral blood mononuclear cells from healthy volunteers or cells of a permanent monoblast cell line were stimulated for 20 h with bacterial lipopolysaccharide and different doses of amrinone. TNF production is suppressed in a dose-dependent manner to a minimum of 9% of controls with 1000 microM of amrinone, reaching half-maximal inhibition at 80 microM amrinone. This effect appears to be mediated via cAMP, which accumulated nearly twofold in the presence of amrinone. Suppression of TNF synthesis by therapeutically administered phosphodiesterase inhibitors such as amrinone may contribute to their beneficial effect in the treatment of heart failure.
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PMID:Amrinone suppresses the synthesis of tumor necrosis factor-alpha in human mononuclear cells. 774 41

Tumor necrosis factor-alpha (TNF-alpha), a monokine that contributes to vascular dysfunction accompanying the host response to gram-negative sepsis, has been shown to increase vascular permeability in vivo and to diminish the barrier function of cultured endothelial cell (EC) monolayers. The studies reported here indicate that a mechanism through which TNF alters EC barrier function involves a reduction in intracellular adenosine 3',5'-cyclic monophosphate (cAMP) content, due in part to increased cyclic nucleotide phosphodiesterase (CNPDE) activities. TNF increased the diffusional transit of [3H]sorbitol, [3H]inulin, and 125I-labeled albumin across confluent bovine aortic EC monolayers. This effect of TNF was both time and dose dependent and occurred in parallel with a fall in EC cAMP. cAMP analogues, such as dibutyryl cAMP (DBcAMP), prevented TNF-induced perturbation of EC barrier function. TNF also mediated another important alteration in the EC phenotype, in that both mRNA and activity of the anticoagulant cofactor thrombomodulin were reduced after exposure of EC to TNF and were normalized by the addition of DBcAMP. EC monolayers exposed to TNF-alpha showed increased cAMP levels when exposed to 3-isobutyl-1-methylxanthine, a nonspecific CNPDE inhibitor. Ion exchange chromatography of cytosol derived from TNF-treated EC consistently showed an approximately 245% increase in phosphodiesterase (PDE) IV (high-affinity, cAMP-specific PDE) activity as identified by rolipram inhibition. PDE II activity was increased by 150% after TNF-alpha treatment of early passage EC, which was identified by cGMP-activated hydrolysis of cAMP. Western and Northern analyses, as well as activity studies, revealed that TNF treatment did not change the amount of PDE IV protein or mRNA but rather increased the specific activity of the isozyme, suggesting that a posttranslational modification had occurred. These data indicate that activation of EC CNPDE activity and decreased intracellular cAMP may represent a mechanism by which TNF increases EC permeability and promotes a procoagulant EC phenotype.
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PMID:TNF modulates endothelial properties by decreasing cAMP. 776 2

Interleukin (IL)-12, interferon (IFN)-gamma, and other inflammatory cytokines play an important role in the pathogenesis of autoimmune insulitis and diabetes in NOD mice, and inhibition of these cytokines is likely to be beneficial. In this study, we found that Pentoxifylline (PTX) and Rolipram (phosphodiesterase [PDE] inhibitors that induce increased intracellular cAMP) can block inflammatory cytokine production. Inhibition of IL-12 and IFN-gamma secretion was demonstrated in macrophages activated with lipopolysaccharide or T-cells stimulated through the CD3/T-cell receptor complex, respectively. Moreover, strong inhibition of IL-12 was demonstrated in vivo in superantigen-immunized mice. Rolipram was inhibitory at concentrations as low as 10(-8) to 10(-7) mol/l, and on a molar basis, it was 100-fold more effective than PTX. Tumor necrosis factor-alpha was also inhibited, but IL-4 was less sensitive to suppression. In NOD mice, both PTX and Rolipram reduced the severity of insulitis and prevented diabetes, with or without cyclophosphamide administration (which precipitates onset of disease). This protection of NOD mice was still apparent over 10 weeks after withdrawal of the drug treatment. It appears that blocking the activity of type IV PDE is sufficient to mediate the effects reported in this study, since Rolipram inhibits only this isoform, unlike PTX (a general inhibitor). PTX and Rolipram may be effective in the treatment of autoimmune diabetes or other conditions characterized by excessive production of inflammatory cytokines.
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PMID:The phosphodiesterase inhibitors pentoxifylline and rolipram prevent diabetes in NOD mice. 956 89

It is now recognized that ultraviolet (UV) radiation is a potent environmental insult capable of interfering with immunity to skin cancers and modifying certain immunologic reactions within both locally irradiated skin and distant, unexposed sites. Exposure to UVB light (290-320 nm) induces a potent cutaneous inflammatory response that involves the infiltration of leukocytes into the dermis as well as the production of proinflammatory cytokines by both resident epidermal keratinocytes and dermal cells. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that has been shown to be a major mediator of UVB light effects on cutaneous immunity. Recent studies have demonstrated that pentoxifylline (PTX), a xanthine-derived phosphodiesterase inhibitor, has the ability to inhibit synthesis of TNF-alpha. To examine the effects of PTX on UVB-mediated cutaneous inflammation, Skh/hr hairless mice were injected intraperitoneally with either phosphate-buffered saline or 50 microg/g PTX 1 h before exposure to 2240 J/m2 UVB. Reverse transcription-polymerase chain reaction and immunohistochemical techniques were used to demonstrate that 24 h to 1 wk after UVB-light irradiation, PTX inhibited UVB-induced TNF-alpha gene expression, inhibited the increase in epidermal TNF-alpha protein synthesis, blocked the increase in epidermal proliferation observed after exposure to UVB light, and decreased production of myeloperoxidase by neutrophils infiltrating into the dermis. These studies demonstrated that PTX modifies epidermal responses after acute UVB light exposure and suggest that PTX treatment may be used clinically to modulate the deleterious effects of long-term UVB-light irradiation.
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PMID:Inhibitory effects of pentoxifylline on ultraviolet B light-induced cutaneous inflammation. 960 97

Tumor necrosis factor-alpha (TNF) is known to inhibit fat cell development in vitro and to be expressed in adipose tissue suggesting that it may act as an auto-/paracrine regulator of adipose tissue mass in vivo. We demonstrate here that endogenous TNF-mRNA expression of cultured human preadipocytes and adipocytes is suppressed by the unspecific phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), which is frequently used to trigger the differentiation process. As assessed by the measurement of glycerophosphate dehydrogenase, IBMX stimulated the differentiation of human preadipocytes in a dose dependent manner up to threefold but remained ineffective when cells were simultaneously treated with 1 nM TNF. These results suggest that the adipogenic effect of IBMX is mediated by suppression of endogenous TNF production.
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PMID:The phosphodiesterase inhibitor IBMX suppresses TNF-alpha expression in human adipocyte precursor cells: a possible explanation for its adipogenic effect. 1043 23

Tumor necrosis factor-alpha (TNF-alpha) has a central role in inflammation and is modulated by prostaglandin E(2) (PGE(2)) and cyclic adenosine monophosphate (cAMP). Using microarray, quantitative real-time polymerase chain reaction (qRT-PCR), and protein detection techniques, we showed that ketorolac and rofecoxib had no significant effect on TNF-alpha gene expression in oral mucosal biopsies 3 h after surgery. They both, however, downregulated the gene and protein expression of phosphodiesterase type 4 (PDE4D), which might represent a novel mechanism contributing to their analgesic and anti-inflammatory effects.
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PMID:COX inhibitors downregulate PDE4D expression in a clinical model of inflammatory pain. 1828 87

Tumor necrosis factor-alpha (TNF-alpha) is known to have numerous biological properties relating to inflammation. This cytokine participates in the tissue damage of chronic inflammatory, autoimmune and infectious diseases. Pentoxifylline is a methylxanthine that inhibits phosphodiesterase IV, which inhibits the degradation of the cAMP and prostanoids. The increased intracellular concentration of the cAMP leads to a negative regulation of NF-kappaB and NF-AT transcription factors and suppresses TNF-alpha production. This review describes studies that support evidences that TNF-alpha is involved in the pathogenesis of HTLV-1 associated myelopathy and of cutaneous and mucosal leishmaniasis. Additionally, it demonstrates the effect of pentoxifylline in vitro in inhibiting TNF-alpha and IFN-gamma spontaneous production in PBMC from HTLV-1-infected patients, as well as its in vivo effect in inhibiting TNF-alpha in sera from mucosal leishmaniasis patients. Moreover, we review the results of clinical studies from the last 10 years using pentoxifylline to treat HTLV-1 associated myelopathy and cutaneous and mucosal leishmaniasis.
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PMID:Pentoxifylline down modulate in vitro T cell responses and attenuate pathology in Leishmania and HTLV-I infections. 1868 97

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising anticancer agent but cutaneous T lymphoma cells (CTCL) are less sensitive to TRAIL-induced apoptosis. Here, we report that pentoxifylline (PTX), a phosphodiesterase inhibitor, augments TRAIL-mediated apoptosis in HuT-78 and MyLa cells through modulating extrinsic death receptors and intrinsic mitochondria dependent pathways. Our results clearly show that PTX augments TRAIL-mediated activation of caspase-8 and induces cleavage of Bid, although PTX alone cannot activate caspase-8. This is followed by cytochrome c release and subsequent, activation of caspase-9 and caspase-3 and cleavage of poly (ADP ribose) polymerase (PARP). Combined treatment downregulates the expression of various antiapoptotic proteins including c-FLIP, Bcl-xl, cIAP-1, cIAP-2 and XIAP. PTX induces the expression of death receptors DR4 and DR5 on cell surface of both the cell types where c-Jun NH2-terminal kinase (JNK) pathway plays an important role. Moreover, combined silencing of DR4 and DR5 by small interfering RNA abrogates the ability of PTX to induce TRAIL-mediated apoptosis. Thus, this is the first demonstration that PTX can potentiate TRAIL-mediated apoptosis through downregulation of cell survival gene products and upregulation of death receptors.
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PMID:Pentoxifylline augments TRAIL/Apo2L mediated apoptosis in cutaneous T cell lymphoma (HuT-78 and MyLa) by modulating the expression of antiapoptotic proteins and death receptors. 2080 43


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