Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-1 beta, IL-8, IL-6 and TNF alpha, derived from infiltrating leukocytes, are important mediators of inflammation in arthritic and allergic diseases. Heparinized human whole blood was evaluated as a model to study the effects of various classes of antiinflammatory drugs on cytokine release/biosynthesis from leukocytes. Whole blood was stimulated with zymosan A (1.5 mg/ml) or LPS (5 micrograms/ml) for 4 h to induce cytokine release. Dexamethasone was the most potent inhibitor of TNF alpha, IL-1 beta, IL-6 and IL-8 release from LPS stimulated blood leukocytes (IC50s of 0.19, 0.11 microM, 0.16 and 0.07 respectively). In LPS stimulated blood, SKF-86002, a 5-lipoxygenase/cytooxygenasae inhibitor, and rolipram, a PDE IV inhibitor, also inhibited the release of TNF alpha (IC50s of 33 and 11 microM, respectively), IL-1 beta (IC50s of 11 and 30 microM, respectively), IL-6 (IC50s of 56 and > 30, respectively) and IL-8 (IC50s of 6.7 and 15, respectively), whereas isoproterenol (1 microM) inhibited significantly only TNF alpha release. Nonsteroidal antiinflammatory drugs, 5-lipoxygenase inhibitors and immuno-suppressive drugs were inactive at 30 microM against LPS and zymosan A stimulation of cytokine release. Using zymosan A as the stimulus, only SKF-86002 (30 microM) showed significant inhibition of IL-1 beta (-59%). This 4 h human blood assay has the potential to identify novel inhibitors and sites of actions (e.g. transcription, post-transcriptional and secretion) of new antiinflammatory drugs.
 ...
PMID:The effects of antiinflammatory and antiallergic drugs on cytokine release after stimulation of human whole blood by lipopolysaccharide and zymosan A. 856 22

Cyclic AMP (adenosine 3':5'-cyclic monophosphate, cAMP) is an intracellular second messenger that mediates the actions of endogenous hormones and neurotransmitters and also of drugs such as beta-adrenoceptor agonists. The presence of functional beta-adrenoceptors on human airway epithelial cells has been demonstrated but the expression of the cAMP-metabolizing enzyme, cyclic nucleotide phosphodiesterase (PDE) in these cells has not been studied. We investigated the profile of activity of the different PDE isoenzymes in lysates of a pulmonary epithelial cell line, A549, and of human bronchial epithelial (HBE) cells grown in primary culture. The effects of non-selective and isoenzyme-selective PDE inhibitors on beta-agonist-induced elevations in intracellular cAMP concentrations and the production of interleukin (IL) 8 and prostaglandin (PG) E2 was also investigated. A549 cells expressed a high level of PDE4, lower levels of PDE1 and PDE3, and minor PDE5 activity. Primary HBE cultures expressed PDE4 and PDE1 activity at approximately equal levels with small additional PDE3 and PDE5 activities. The total PDE activity of the HBE cells was approximately nine-fold lower than that of A549 cells. The beta-adrenoceptor agonist salbutamol, caused a slow, concentration-dependent increase in intracellular cAMP levels in HBE cells which was not affected by a non-selective PDE inhibitor, IBMX (100 microM), or by a selective PDE4 inhibitor, rolipram (100 microM). Zardaverine, a dual-selective PDE3/PDE4 inhibitor, had no effect on cAMP levels at 10 microM but did cause a significant enhancement of salbutamol-induced elevations at 100 microM (150+/-36 pmol/10(5) cells at 10 microM salbutamol vs. 64+/-25 pmol/10(5) cells in the absence of zardaverine; n=3,P<0.01). Neither basal nor tumour necrosis factor alpha (10 ng/ml)-induced IL8 secretion was affected by salbutamol (10 microM) in the absence or presence of IBMX (100 microM). Salbutamol (10 microM), alone or in the presence of IBMX (100 microM) or rolipram (100 microM), also failed to affect basal or bradykinin (1 microM)-induced PGE2 release. Zardaverine (100 microM) caused a significant increase in basal PGE2 release but this was not enhanced in the presence of salbutamol (10 microM) and was not related to changes in cAMP levels. We conclude that HBE cells express a low total PDE activity, made up predominantly of PDE1 and PDE4 isoenzymes, and that intracellular cAMP levels in HBE cells are not related to the production of IL8 or PGE2.
 ...
PMID:Cyclic nucleotide phosphodiesterase in human bronchial epithelial cells: characterization of isoenzymes and functional effects of PDE inhibitors. 980 63

The aim of reverse pharmacognosy is to find new biological targets for natural compounds by virtual or real screening and identify natural resources that contain the active molecules. To demonstrate the applicability of this concept, we report here a study on epsilon-viniferin, an active ingredient for cosmetic development. Nevertheless, this natural substance is weakly defined in terms of biological properties. SELNERGY, an inverse docking computer software, was used to identify putative binding biological targets for epsilon-viniferin. Among the 400 screened proteins two targets were retained. For cosmetic application, cyclic nucleotide phosphodiesterase 4 (PDE4) was the most interesting candidate. Moreover, other PDE subtypes (1, 2, 3, 5 and 6) were not retained, indicating a selectivity for PDE4. The experimental binding tests on the 6 subtypes of PDE revealed a significant selectivity of epsilon-viniferin for the PDE4 subtype. This selectivity was confirmed by evaluation of epsilon-viniferin on the secretion of TNF-alpha and Interleukin-8. Our data demonstrated that epsilon-viniferin possesses anti-inflammatory properties by inhibiting PDE4 subtype. In conclusion, reverse pharmacognosy and its inverse docking component cannot only be integrated into a program for new lead discovery but is also a useful approach to find new applications for identified compounds.
 ...
PMID:Reverse pharmacognosy: application of selnergy, a new tool for lead discovery. The example of epsilon-viniferin. 1647 25

Phosphodiesterase type 4 (PDE(4)) inhibitors are currently being evaluated as potential therapies for inflammatory airway diseases. However, this class of compounds has been shown to cause an arteritis/vasculitis of unknown etiology in rats and cynomolgus monkeys. Studies in rodents have demonstrated the anti-inflammatory effects of PDE(4) inhibitors on lipopolysaccharide (LPS)-induced airway inflammation. The aim of this work was to assess the direct effects of PDE(4) inhibitors on inflammatory cells and cytokine levels in the lung in relation to therapeutic effects. The effects of the PDE(4) inhibitors 3-cyclo-propylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide (roflumilast) and 3-(cyclopentyloxy)-N-(3,5-dichloro-4-pyridyl)-4-methoxybenzamide (piclamilast) were assessed in vivo, using BALB/c mice, and in vitro, in unstimulated human endothelial and epithelial cell lines. In BALB/c mice, LPS challenge caused an increase in neutrophils in bronchoalveolar lavage (BAL) and lung tissue and BAL tumor necrosis factor-alpha levels, which were inhibited by treatment with either roflumilast or piclamilast (30-100 mg/kg subcutaneously). However, roflumilast and piclamilast alone (100 mg/kg) caused a significant increase in plasma and lung tissue keratinocyte-derived chemokine (KC) levels, and lung tissue neutrophils. In vitro, both piclamilast and roflumilast caused an increase in interleukin (IL)-8 release from human umbilical vein endothelial cells but not BEAS-2B cells, suggesting that one source of the increased KC may be endothelial cells. At doses that antagonized an LPS-induced inflammatory response, the PDE(4) inhibitors possessed proinflammatory activities in the lung that may limit their therapeutic potential. The proinflammatory cytokines KC and IL-8 therefore may provide surrogate biomarkers, both in preclinical animal models and in the clinic, to assess potential proinflammatory effects of this class of compounds.
 ...
PMID:Phosphodiesterase type 4 inhibitors cause proinflammatory effects in vivo. 1686 99

Reactive oxygen species (ROS) have been implicated in various pulmonary diseases by causing direct injury to lung epithelial cells. Signalling activity of cells through transcription factors such as nuclear factor kappa B (NF-kappaB) and AP-1 have been shown to be regulated by ROS, and the release of pro-inflammatory cytokines demonstrated in the study of inflammatory disease. In this study, we examined the effect of the oxidant tert-butylhydroperoxide (tBHP) on mouse J774 macrophages and its ability to cause the release of the pro-inflammatory cytokine tumour necrosis factor alpha (TNF-alpha). The role of calcium as a signalling molecule was studied using various calcium antagonists. The role of the signalling molecule cAMP was also investigated using phosphodiesterase inhibitors PDE1 and PDE4 families. Oxidative stress was investigated in lung epithelial (A549) cells with and without calcium antagonists and PDE inhibitors with regard to their ability to modulate release of the neutrophil chemoattractant interleukin 8 (IL-8). The oxidant tBHP significantly increased the cytosolic calcium concentration in J774 macrophages, which was prevented by the PDE1 inhibitor. The production of TNF-alpha protein by J774 macrophages was mediated by a pathway involving calcium as addition of calcium antagonists inhibited the tBHP stimulated increase in the cytokine. Inhibitors of both PDE1 and PDE4 completely prevented the tBHP stimulated TNF-alpha release suggesting that the cAMP pathway may be important in the oxidant induced signalling pathway leading to gene expression of pro-inflammatory cytokines. In the presence of oxidant alone, A549 epithelial cells released significant amounts of IL-8, which was inhibited by both calcium antagonist treatment and PDE inhibition treatment. These data suggest that ROS-mediated lung inflammation could be mediated at least in part by calcium and elevated PDE activity associated with decreased cAMP in both macrophages and epithelial cells. Inhibition of these pathways may provide a route for treatment of inflammatory lung diseases.
 ...
PMID:The effect of oxidative stress on macrophages and lung epithelial cells: the role of phosphodiesterases 1 and 4. 1712 90