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)

Tumour necrosis factor-alpha (TNF) plays a pivotal role in acute and chronic inflammatory processes. It has been demonstrated that TNF is a mediator in inflammatory bowel disease. In the past different pharmacological approaches have been identified to suppress TNF synthesis in lipopolysaccharide-stimulated human mononuclear cells by cAMP-elevating agents. In the present study we examine whether TNF synthesis in the colon underlies similar regulatory mechanisms as in mononuclear cells. We therefore established a short-time organ culture of rat caecum. In this model we obtained maximal TNF formation of 159 pg/ml after a 7-h incubation period, as determined by L929 bioassay. The formation of bioactive TNF was confirmed by the application of neutralizing TNF antibody in the L929 bioassay and by immunodot blot. Lipopolysaccharide and pokeweed mitogen did not further enhance TNF synthesis. In contrast, TNF production was suppressed to 25% of control by 5 micrograms/ml hydrocortisone. Unexpectedly, the specific type IV phosphodiesterase inhibitor rolipram and cicaprost, a stable prostacyclin analogue, did not achieve significant suppression of TNF synthesis in this model. The present study defines an experimental model to investigate ex vivo TNF synthesis in rat colonic tissue. Applying this model, cAMP-elevating agents are identified as poor candidates for TNF-suppressing strategies in inflamed colon.
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PMID:Synthesis of tumour necrosis factor-alpha in tissue culture of rat caecum: lack of suppression by phosphodiesterase inhibitors and prostanoids. 885 58

1. Expression of cell adhesion molecules (CAM) on the lung microvascular endothelium is believed to play a key role in the recruitment of leukocytes in pulmonary inflammation. Moreover, regulation of CAM expression may be an important mechanism through which this inflammation may be controlled. Experimental evidence has suggested that combined phosphodiesterase (PDE) 3 and 4 inhibitors increase cyclic AMP levels within cells greater than inhibition of either isoenzyme alone. In the present study we assessed the effect of combinations of rolipram (PDE4 inhibitor), ORG 9935 (PDE3 inhibitor) and salbutamol (beta-agonist) on CAM expression and neutrophil or eosinophil adhesion to human lung microvascular endothelial cells (HLMVEC). 2. Tumour necrosis factor-alpha (TNF-alpha)-induced intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and E-selectin expression were measured on HLMVEC monolayers at 6 h by a specific ELISA technique in the presence of different combinations of medium, rolipram, ORG 9935 and salbutamol. 3. Rolipram in combination with salbutamol, but neither agent alone, inhibited TNF-alpha-induced E-selectin expression, whilst ICAM-1 and VCAM-1 expression were not affected. ORG 9935 had no significant effect on CAM expression alone. However, in combination with rolipram a syngergistic inhibition of VCAM-1 and E-selectin, but not ICAM-1, expression was observed. No further inhibition was seen in the additional presence of salbutamol. 4. Neutrophil adhesion to TNF-alpha-stimulated (6 h) HLMVEC was mainly E-selectin dependent in this model, as ENA2 an anti-E-selectin monoclonal antibody (mAb) abrogated neutrophil adhesion. Eosinophil adhesion was E-selectin-, ICAM-1- and VCAM-1-dependent, as assessed by the inhibitory activity of ENA2 and the ability of a mAb to the ICAM-1 ligand, CD18, and a mAb to the VCAM-1 ligand, VLA4, to attenuate adhesion. 5. Rolipram in the presence of salbutamol or ORG 9935 significantly inhibited neutrophil adherence to TNF-alpha-stimulated HLMVEC. Eosinophil adherence to monolayers was inhibited only when HLMVEC were activated in the presence of rolipram and ORG 9935. 6. Collectively, the findings presented in this manuscript suggest that inhibition of PDE4 with appropriate activation of adenylate cyclase is sufficient to inhibit induction of E-selectin expression on HLMVEC to a level that has functional consequences for neutrophil adhesion. In contrast, combined inhibition of PDE3 and 4 isoenzymes is necessary to inhibit VCAM-1 and to have inhibitory effects on eosinophil adhesion to activated HLMVEC. Upregulation of ICAM-1 expression on HLMVEC does not appear to be modulated by PDE3 and 4 inhibition. These data may have implications for the use of selective PDE4 inhibitors in lung inflammation.
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PMID:Modulation of cell adhesion molecule expression and function on human lung microvascular endothelial cells by inhibition of phosphodiesterases 3 and 4. 963 Mar 64

Tumour necrosis factor/cachecin (TNF-alpha) and lymphotoxin (LTalpha / TNF-alpha), 2 members of the TNF family of cytokines, have numerous biological functions, such as induction of apoptosis, cytotoxicity, inflammation, immunoregulation, proliferation and antiviral responses. Although TNF-alpha is produced by many cell types, the majority comes from activated macrophages. The related molecule, LT-alpha is produced mainly by activated lymphocytes and shares many of TNF's properties. TNF-alpha is active in both of its molecular forms, a secreted 17 kDa mature form and a transmembrane 26 kDa precursor. It induces activity by stimulating 2 distinct receptor subtypes, TNFR1 (55 kDa) and TNFR2 (75 kDa). The activation of TNFR1 is generally thought to trigger the majority of inflammatory and apoptotic effects, although TNFR2 has recently been shown to play more of a role in signal transduction than was initially thought. TNF-alpha is responsible for the induction of apoptosis in certain cell types, where it plays a pivotal role in the induction of cytotoxicity, killing of neoplastic cells and deletion of autoreactive T-cell clones. This cytokine, and in particular, its overproduction, has been implicated in the pathogenesis of a variety of immunologically mediated inflammatory diseases, including endotoxic shock, inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA). Currently, there is an intense effort underway to regulate TNF-alpha production and activity, in order to treat diseases where TNF-alpha is thought to be pathologically indicated. To achieve this goal, the pharmaceutical industry is currently pursuing a 2 pronged strategy: a) testing biological agents such as antibodies against TNF-alpha or soluble TNF-alpha receptor constructs, and b) identifying small molecular inhibitors directed against targets such as phosphodiesterase-IV (PDE-IV) and TNF-alpha converting enzyme (TACE), a subgroup of the matrix metalloproteinases (MMP). The main difficulties in the clinical implementation of the biological agents are: development of immunogenicity, lack of oral availability and the high cost of production. The currently available small molecular compounds exhibit poor bio-availability and low selectivity, resulting in unacceptable side effects and a low therapeutic index. Despite these hurdles, numerous companies are actively pursuing agents that inhibit TNF-alpha.
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PMID:AntiTNF-alpha agents in the treatment of inflammation. 1599 32