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At least 811 records · Page 45Linked to original sources
PubMed2002

The PYRIN-CARD protein ASC is an activating adaptor for caspase-1.

The PYRIN and CARD domains are members of the six-helix bundle death domain-fold superfamily that mediates assembly of large signaling complexes in the apoptotic and inflammatory signaling pathways. Here we show that the PYRIN-CARD protein ASC functions as a caspase-1-activating adaptor. ASC interacted specifically with procaspase-1 via CARD-CARD interactions and induced its oligomerization. Consistent with these results ectopic expression of full-length ASC, but not its isolated CARD or PYRIN domain, with procaspase-1 induced activation of procaspase-1 and processing of pro-interleukin-1beta in transfected cells. Substitution of the PYRIN domain of ASC with an inducible FKBP12 oligomerization domain produced a molecule that can induce caspase-1 activation in response to stimulation with the oligomerization drug AP20187, suggesting that the PYRIN domain functions as an oligomerization domain, whereas the CARD domain functions as the effector domain in the caspase-1 activation pathway. Furthermore stable expression of an isolated CARD of ASC in THP-1 cells diminished interleukin-1beta generation in response to pro-inflammatory cytokines. These results indicate that ASC is involved in the caspase-1 signaling pathway by mediating the assembly of a caspase-1-inflammasome signaling complex in response to pro-inflammatory cytokine stimulation.

Blood Proteins↗
PubMed2026

Multi-omics integration uncovers adaptive responses of stomach and pyloric ceca to artificial feed in mandarin fish (Siniperca chuatsi).

The mandarin fish, as an obligate piscivore, is highly dependent on live bait, which restricts its intensive aquaculture. Although domestication has enabled it to partially accept formulated diets, the tissue-specific molecular adaptation mechanisms of its digestive tract to artificial feed remain unclear. In this study, we conducted an integrated analysis of mandarin fish fed with live bait or artificial diet for three weeks, combining growth performance evaluation, gastric histology, and paired transcriptomic and metabolomic analyses of the stomach and pyloric ceca. AD feeding significantly improved growth performance, while histological examination revealed marked hyperplasia of the gastric mucosa and disorganized fold structures. Transcriptomic analysis identified 5065 and 3381 differentially expressed genes in the stomach and pyloric ceca, respectively. In the stomach, the artificial diet induced a glutathione-dependent antioxidant response, accompanied by glycolytic reprogramming and coordinated upregulation of genes in the extracellular matrix (ECM)-receptor interaction signaling pathway, including those encoding collagen, laminin, and integrin. In the pyloric ceca, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation were broadly suppressed, whereas glycosaminoglycan degradation and lysosomal pathways were activated. Metabolomic analysis showed that gastric metabolites were enriched in vascular and inflammatory mediator pathways, while metabolites in the pyloric ceca were enriched in peroxisome proliferator-activated receptor (PPAR) signaling, sphingolipid signaling, and steroid hormone biosynthesis pathways. Following artificial diet feeding, integrated multi-omics analysis of the stomach revealed significant enrichment of pathways such as phospholipase D signaling, sphingolipid signaling, and arachidonic acid metabolism, accompanied by the accumulation of key metabolites including sphingosine-1-phosphate, 20-hydroxyeicosatetraenoic acid, and cellobiose. Integrated analysis of the pyloric ceca identified significantly altered pathways, including sphingolipid metabolism, alpha-linolenic acid metabolism, and glutathione metabolism, along with elevated levels of sphingosine-1-phosphate, sphingosine galactoside, and 9-hydroxy-12-oxo-10,15-octadecadienoic acid, as well as decreased glutathionylspermidine. These findings systematically unveil the tissue-specific molecular adaptation characteristics of the mandarin fish digestive tract in response to artificial feed, providing an important basis for understanding the molecular mechanisms of dietary adaptation in carnivorous fish and for optimizing artificial feed formulations.

Animals↗
PubMed2003

Hydroxyethyl starch inhibits NF-kappaB activation and prevents the expression of inflammatory mediators in endotoxic rats.

Hydroxyethyl starch (HES) has been shown to be beneficial in several inflammatory situations, but the mechanisms are unclear. The present study tested the hypothesis that HES has effects on nuclear factor kappa B (NF-kappaB) activation and the expression of inflammatory mediators induced by lipopolysaccharide. Sepsis was induced in male Wistar rats by injection of lipopolysaccharide (LPS, 6 mg/kg, i.p.). At 1 min after the LPS challenge, HES was infused via the right external jugular vein at the following doses: 3.75, 7.5, 15, or 30 ml/kg. NF-kappaB activation in peripheral blood mononuclear cells and neutrophils, plasma concentrations of tumor necrosis factor (TNF)-alpha, cytokine-induced neutrophil chemoattractant (CINC), expression of CD11b on the blood neutrophil cell surface, and neutrophil sequestration in multiple organs were examined 2 or 4 hr after the LPS challenge. Treatment of rats with HES (3.75 and 7.5 ml/kg) prevented LPS-induced NF-kappaB activation, and inhibited, in a dose-related manner, LPS-induced TNF-alpha and CINC expression. The 4 graded doses of HES decreased CD11b expression in a dose-dependent manner. HES significantly reduced neutrophil sequestration in lung, heart, and liver. These results suggest that HES has an anti-inflammatory effect in endotoxic rats. This effect is mediated by inhibition in the production pathways for inflammatory mediators, including NF-kappaB activation.

Animals↗
PubMed2004

Post-transcriptional and nongenomic effects of glucocorticoids.

The ability of glucocorticoids to interfere with post-transcriptional gene regulation has recently been recognized as a potentially important part of their anti-inflammatory property, and the mechanisms governing such activity are under active investigation. Several studies have shown that glucocorticoids can inhibit inflammatory signaling pathways known to control mRNA turnover and translation. Moreover, several glucocorticoid-sensitive determinants have been identified on mRNA molecules of inflammatory genes, and the RNA-binding factors interacting with them might constitute relevant glucocorticoid targets. Glucocorticoids also exert effects characterized as nongenomic, which occur within minutes of drug administration. The mechanisms of action of nongenomic glucocorticoid effects differ from the classical, transcription-dependent glucocorticoid action and involve the production of second-messenger molecules and activation of signal transduction pathways, either by the nuclear glucocorticoid receptor or by a membrane glucocorticoid receptor that has not yet been fully characterized. Ultimately, the discovery of novel pathways involved in mediating the actions of glucocorticoids should lead to improved targets for anti-inflammatory therapy.

Gene Expression Regulation↗
PubMed2005

Signal transduction pathways and transcription factors as therapeutic targets in inflammatory disease: towards innovative antirheumatic therapy.

Many chronic inflammatory diseases are associated with deregulated intracellular signal transduction pathways. Resultant pathogenic interactions between immune and stromal cells lead to changes in cell activation, proliferation, migratory capacity, and cell survival that all contribute to inflammation. Increasing efforts are now being made in the design of novel therapeutic compounds to interfere with signaling pathways in inflammatory diseases like rheumatoid arthritis (RA). In this review we will outline the major signal transduction pathways involved in the pathogenesis of RA. We will assess advances in targeting a number of key intracellular pathways, including nuclear factor-(kappa)B (NF-(kappa)B), mitogen-associated protein kinases (MAPKs), phosphoinositide 3-kinase (PI3K)/Akt, signal transducers and activators of transcription (STATs), and reactive oxygen species (ROS) production. Finally, we will discuss recently identified lead molecules and the progress of selected compounds towards becoming new drugs for the treatment of inflammatory diseases.

Animals↗
PubMed2005

Signal transducers and activators of transcription 3 signaling pathway: an essential mediator of inflammatory bowel disease and other forms of intestinal inflammation.

Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of chronic inflammatory bowel disease (IBD), are characterized by mucosal immune cell activation that is driven by a cytokine imbalance. Several cytokines involved in IBD act through the activation of the signal transducers and activators of transcription (STAT) family. We investigated the activation of STAT3 in the mucosa of CD and UC patients, and evaluated whether this event is specific for IBD patients. Using immunofluorescence and immunoblotting, total and phosphorylated STAT3 levels were assessed in biopsy specimens, isolated lamina propria mononuclear cells, and peripheral blood mononuclear cells from patients with CD, UC, other forms of intestinal inflammation, and control subjects. Immunoblotting revealed phosphorylated STAT3 in mucosal biopsy specimens from patients with CD, UC, celiac disease, and acute self-limited colitis, but not in the normal mucosa of control subjects. In IBD patients, STAT3 activation was confined to actively inflamed areas. Accordingly, activated STAT3 was detected in isolated lamina propria mononuclear cells from inflamed IBD tissues, but not in peripheral blood mononuclear cells from control subjects or IBD patients. Immunofluorescence demonstrated that the sources of activated STAT3 were macrophages and T lymphocytes, but not neutrophils. STAT3 activation also was detected in T cells infiltrating the duodenal mucosa of celiac disease patients. We conclude that STAT3 signaling occurs in both CD and UC, where it is strictly confined to areas of active inflammation and is limited to infiltrating macrophages and T cells. The occurrence of STAT3 signaling in other acute and chronic intestinal inflammatory conditions suggests that, rather than a specific feature of IBD, it represents a fundamental signaling pathway that is shared by multiple forms of gut inflammation.

Adult↗
PubMed2000

p38-dependent enhancement of cytokine-induced nitric-oxide synthase gene expression by heat shock protein 70.

Heat shock protein (hsp) 70 protects cells against stress by means of its ability to chaperone denatured proteins and to modulate stress-activated signaling pathways. Because inflammatory processes are often accompanied by hsp expression and because stress and cytokines share several signaling pathways, we investigated the possibility that hsp70 might modulate the cellular response to cytokines. We found that stable cell clones overexpressing hsp70, or cells shortly after transfection with hsp70, produced 2 times more nitric oxide and inducible nitric-oxide synthase (iNOS) protein and mRNA in response to cytokines than control cells expressing undetectable amounts of hsp70. Since mitogen-activated protein kinases participate in the activation of iNOS by cytokines, we investigated whether hsp70 affected the activation of these signaling pathways. hsp70 overexpression led to a specific enhancement of the activation of the p38 pathway by cytokines, producing little or no effect on the activation of extracellular signal-regulated kinase or Jun N-terminal kinase. Blocking p38 activity with SB203580 totally abolished the enhancing effect of hsp70 on cytokine-induced endogenous iNOS mRNA accumulation or transcription of an iNOS promoter-driven luciferase gene, while having little effect on the cytokine response observed in control cells. We conclude that the p38 pathway acts as an enhancing factor in the activation of iNOS by cytokines and that hsp70 can modulate the cellular response to cytokines by acting on signaling elements upstream of p38.

Animals↗
PubMed2005

Lipoxin analogs: novel anti-inflammatory mediators.

Most pharmacological anti-inflammatory agents are designed to inhibit the enzymes or receptors that are directly involved in mediating inflammation. In contrast, lipoxin analogs utilize an entirely different anti-inflammatory paradigm, namely that of activating the endogenous anti-inflammatory signaling pathways by which inflammation is normally resolved. Specifically, synthetic stable analogs of the endogenous anti-inflammatory eicosanoid lipoxin A4 (LXA4) have been shown to mimic the anti-inflammatory actions of LXA4 in a variety of inflammation models and display desirable pharmacological properties, especially their high oral bioavailability. Lipoxin analogs could be potentially useful for a wide array of disease states that have an inflammatory component, and look particularly promising for treatment of inflammatory bowel disease.

Animals↗
PubMed2006

The inflammatory response in stroke.

Recent works in the area of stroke and brain ischemia has demonstrated the significance of the inflammatory response accompanying necrotic brain injury. Acutely, this response appears to contribute to ischemic pathology, and anti-inflammatory strategies have become popular. This chapter will discuss the current knowledge of the contribution of systemic and local inflammation in experimental stroke. It will review the role of specific cell types including leukocytes, endothelium, glia, microglia, the extracellular matrix and neurons. Intracellular inflammatory signaling pathways such as nuclear factor kappa beta and mitogen-activated protein kinases, and mediators produced by inflammatory cells such as cytokines, chemokines, reactive oxygen species and arachidonic acid metabolites will be reviewed as well as the potential for therapy in stroke and hypoxic-ischemic injury.

Animals↗
PubMed2005

Androgens regulate the immune/inflammatory response and cell survival pathways in rat ventral prostate epithelial cells.

A major hurdle in understanding the role of androgens is the heterogeneity of androgen receptor (AR) expression in the prostate. Because the majority of prostate cancer arises from the AR-positive secretory luminal epithelial cells, identifying the androgen-mediated pathways in the prostate epithelium is of great significance to understanding their role in prostate pathogenesis. To meet this objective, the current study was designed to identify immediate-early genes expressed in response to the synthetic androgen R1881 in cultured rat ventral prostate epithelial cells. Rat ventral prostate epithelial cells, purified from 20-d-old rats, were cultured, and the presence of AR and the response to androgen were established. The cells were then treated with R1881 for 2 and 12 h to capture immediate-early genes in an Affymetrix-based gene chip platform. A total of 66 nonredundant genes were identified that were responsive to R1881. The functional androgen response elements were identified in the proximal promoter to determine possible molecular mechanism. Cluster analysis identified five distinct signatures of R1881-induced genes. Pathway analysis suggested that R1881 primarily influences cell proliferation/differentiation and inflammatory/immune response pathways. Androgens appear to regulate cell renewal by regulating differentiation, cell proliferation, and apoptosis. Two mutually exclusive inflammatory response pathways were observed. The interferon pathway was up-regulated, and the ILs were down-regulated. The data identified novel androgen-regulated genes (e.g. Id1, Id3, IL-6, IGF-binding protein-2 and -3, and JunB). The loss of androgen regulation of these genes can have important consequences for cellular transformation and transition to androgen-independent growth and survival.

Androgens↗
PubMed2007

[p38 MAPK/cPLA2 pathway mediates interleukins release in inflammatory cell model].

OBJECTIVE: To explore the underlying mechanism of lipopolysaccharide (LPS)-induced interleukin-1 beta (IL-1 beta) and IL-6 release via p38 mitogen-activated protein kinase (MAPK) pathway in HeLa cells for further identification of involved down-stream message factors. METHODS: HeLa cells were challenged with LPS to reproduce inflammatory cell model. The activity or expression of p38 MAPK, cytosolic phospholipase A(2) (cPLA(2)) and COX-2, was inhibited with pretreatment of inflammatory HeLa cells with the inhibitors (SB203580, AACOCF(3), NS-398) or transfected with the cPLA(2) antisense oligonucleotide (SK7111), then the activities and/or expression of p38 MAPK, cPLA(2), COX-2, and relationship with levels of IL-1 beta and IL-6 supernatants were determined in each group. RESULTS: SB203580 obviously down-regulated the activities of p38 and cPLA(2), as well as the release of IL-1 beta and IL-6. AACOCF(3) and SK7111 blocked dose-dependently the activity or expression of cPLA(2), IL-1 beta and IL-6 production. However, the expression of COX-2 could hardly be detected in HeLa cells, even after LPS treatment. At the same time, pre-treatment with NS-398 had no effect on IL-1 beta, IL-6 production. CONCLUSION: p38 MAPK/cPLA(2) pathway mediates the expression of IL-1 beta and IL-6 resulting from LPS treatment of HeLa cells, while COX-2, as a down-stream enzyme of cPLA(2) has no effect in this process.

Cyclooxygenase 2↗
PubMed2002

Nitric oxide-scavenging properties of some chalcone derivatives.

The implication of NO in many inflammatory diseases has been well documented. We have previously reported that some chalcone derivatives can control the iNOS pathway in inflammatory processes. In the present study, we have assessed the NO-scavenging capacity of three chalcone derivatives (CH8, CH11, and CH12) in a competitive assay with HbO(2), a well-known physiologically relevant NO scavenger. Our data identify these chalcones as new NO scavengers. The estimated second-order rate constants (k(s)) for the reaction of the three derivatives with NO is in the same range as the value obtained for HbO(2), with CH11 exerting the greatest effect. These results suggest an additional action of these compounds on NO regulation.

Chalcone↗
PubMed2002

The epithelial cell cytoskeleton and intracellular trafficking. V. Polarized compartmentalization of antigen processing and Toll-like receptor signaling in intestinal epithelial cells.

The intestinal epithelial cell (IEC) is exposed at the apical surface to a high concentration of foreign antigen and bacterial products capable of triggering inflammatory responses. Complex intracellular pathways of antigen trafficking and the polarized expression of immunologically active receptors provide additional means to regulate the inflammatory pathways in these cells. In the case of human leukocyte antigen (HLA) class II heterodimers, surface expression is highly restricted to the basolateral surface, and this also appears to be the case for Toll-like receptor 5 (TLR5) on polarized T84 human colon cancer cells. Processing of soluble antigen via HLA class II in IEC can occur following internalization from the apical surface but is highly inefficient. In addition, certain bacteria can facilitate the transport of flagellin (the ligand for TLR5) across an intact epithelium. Disruption of the tight junctions between IECs, allowing direct access of antigen and flagellin to the basolateral surface of the cell, dramatically affects the functional outcome HLA class II and TLR5 pathways.

Animals↗
PubMed2000

Oxidants, nitrosants, and the lung.

The respiratory tract is subjected to a variety of environmental stresses, including oxidizing gases, particulates, and airborne microorganisms, that together, may injure structural and functional lung components and thereby jeopardize the primary lung function of gas exchange. To cope with such various environmental threats, the lung has developed elaborate defense mechanisms that include inflammatory-immune pathways as well as several antioxidant systems. These defense systems operate largely in extracellular spaces, thus protecting underlying bronchial and alveolar epithelial cells from injury, although these cells themselves are also active participants in such (inflammatory) defense mechanisms. Although potentially harmful, oxidants are increasingly recognized as pathophysiologic mediators produced primarily by inflammatory-immune cells as a host defense mechanism, but also by various other cell types as an intracellular mediator in various cell responses, thus affecting inflammatory-immune processes or inducing resistance. The molecular mechanisms and signaling pathways involved in such processes are the focus of much current investigation. Nitric oxide, a messenger molecule produced by many lung cell types, also modulates oxidant-mediated processes, thereby giving rise to a new family of reactive nitrogen species ("nitrosants") with potentially unique signaling properties. The complex role of oxidants and nitrosants in various pathophysiologic processes in the lung have confounded the design of therapeutic approaches with antioxidant substrates. This review discusses current knowledge regarding extracellular antioxidant defenses in the lung, and oxidant/nitrosant mechanisms operating under inflammatory-immune conditions and their potential contribution to common lung diseases. Finally, some recent developments in antioxidant therapeutic strategies are discussed.

Antioxidants↗
PubMed2005

Attenuated rabies virus activates, while pathogenic rabies virus evades, the host innate immune responses in the central nervous system.

Rabies virus (RV) induces encephalomyelitis in humans and animals. However, the pathogenic mechanism of rabies is not fully understood. To investigate the host responses to RV infection, we examined and compared the pathology, particularly the inflammatory responses, and the gene expression profiles in the brains of mice infected with wild-type (wt) virus silver-haired bat RV (SHBRV) or laboratory-adapted virus B2C, using a mouse genomic array (Affymetrix). Extensive inflammatory responses were observed in animals infected with the attenuated RV, but little or no inflammatory responses were found in mice infected with wt RV. Furthermore, attenuated RV induced the expression of the genes involved in the innate immune and antiviral responses, especially those related to the alpha/beta interferon (IFN-alpha/beta) signaling pathways and inflammatory chemokines. For the IFN-alpha/beta signaling pathways, many of the interferon regulatory genes, such as the signal transduction activation transducers and interferon regulatory factors, as well as the effector genes, for example, 2'-5'-oligoadenylate synthetase and myxovirus proteins, are highly induced in mice infected with attenuated RV. However, many of these genes were not up-regulated in mice infected with wt SHBRV. The data obtained by microarray analysis were confirmed by real-time PCR. Together, these data suggest that attenuated RV activates, while pathogenic RV evades, the host innate immune and antiviral responses.

Animals↗
PubMedDate not supplied

L-Buthionine-(S,R)-sulfoximine, an irreversible inhibitor of gamma-glutamylcysteine synthetase, augments LPS-mediated pro-inflammatory cytokine biosynthesis: evidence for the implication of an IkappaB-alpha/NF-kappaB insensitive pathway.

The pro-inflammatory cytokines, including tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, contribute to the exacerbation of pathophysiological conditions in the lung. The regulation of cytokines involves the reduction-oxidation (redox)-sensitive nuclear factor-kappaB (NF-kappaB), the activation of which is mediated through an upstream kinase that regulates the phosphorylation and subsequent degradation of inhibitory-kappaB (IkappaB)-alpha, the major cytosolic inhibitor of NF-kappaB. It was hypothesized that lipopolysaccharide (LPS)-induced biosynthesis of TNF-alpha and IL-6 in vitro is tightly regulated by redox equilibrium. Furthermore, the likely involvement of the IkappaB-alpha/NF-kappaB signalling transduction pathway in mediating redox-dependent regulation of LPS-induced cytokine biosynthesis was revealed. Using alveolar epithelial cells, the role of L-buthionine-(S,R)-sulfoximine (BSO), a specific and irreversible inhibitor of gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme in glutathione (GSH - an antioxidant thiol) biosynthesis, in regulating LPS-mediated TNF-alpha and IL-6 production and the IkappaB-alpha/NF-kappaB signalling pathway was investigated. Pre-treatment with BSO, prior to exposure to LPS augmented, in a dose-dependent manner, LPS-induced TNF-alpha and IL-6 biosynthesis, an effect associated with the induction of intracellular accumulation of reactive oxygen species (ROS). Interestingly, BSO blocked the phosphorylation of IkappaB-alpha, reduced its degradation, thereby allowing its cytosolic accumulation, and subsequently inhibited the activation of NF-kappaB. These results indicate that there are ROS and redox-mediated effects regulating pro-inflammatory cytokines, and that the IkappaB-alpha/NF-kappaB pathway is redox-sensitive and differentially involved in mediating redox-dependent regulation of cytokine signaling.

Animals↗
PubMed2000

Induction of decay-accelerating factor by thrombin through a protease-activated receptor 1 and protein kinase C-dependent pathway protects vascular endothelial cells from complement-mediated injury.

There is increasing evidence for functional crosstalk between inflammatory and thrombotic pathways in inflammatory vascular diseases such as atherosclerosis and vasculitis. Thus, complement activation on the endothelial cell (EC) surface during inflammation may generate thrombin via the synthesis of tissue factor. We explored the hypothesis that thrombin induces EC expression of the complement-regulatory proteins decay-accelerating factor (DAF), membrane cofactor protein (MCP), and CD59 and that this maintains vascular integrity during coagulation associated with complement activation. Thrombin increased DAF expression on the surface of ECs by 4-fold in a dose- and time-dependent manner as measured by flow cytometry. DAF up-regulation was first detectable at 6 hours and maximal 24 hours poststimulation, whereas no up-regulation of CD59 or MCP was seen. Thrombin-induced expression required increased DAF messenger RNA and de novo protein synthesis. The response depended on activation of protease-activated receptor 1 (PAR1) and was inhibited by pharmacologic antagonists of protein kinase C (PKC), p38 and p42/44 mitogen-activated protein kinase, and nuclear factor-kappa B. The increased DAF expression was functionally relevant because it significantly reduced C3 deposition and complement-mediated EC lysis. Thus, thrombin-generated at inflammatory sites in response to complement activation-is a physiologic agonist for the PKC-dependent pathway of DAF regulation, thereby providing a negative feedback loop protecting against thrombosis in inflammation. (Blood. 2000;96:2784-2792)

CD55 Antigens↗
PubMed1984

Nonsteroidal anti-inflammatory drugs stimulate 15-lipoxygenase/leukotriene pathway in human polymorphonuclear leukocytes.

[14C]Arachidonic acid metabolism in human polymorphonuclear (PMN) leukocytes proceeds predominantly through the 5- and 15-lipoxygenase pathways. The major products are 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) and 15-HETE. Three nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit 5-HETE production. Concentrations of drugs required for 50% inhibition of 5-lipoxygenase were 0.17mM for indomethacin, 0.60mM for ibuprofen, and 3.4mM for aspirin. A surprising result was that the human PMN leukocyte 15-lipoxygenase/leukotriene pathway was selectively activated by 1mM to 5mM ibuprofen. Metabolites were identified by gas chromatography/mass spectrometry or by retention times on high-performance liquid chromatography in comparison with authentic standards. The major product was 15-HETE; in all 19 human donors tested, 15-HETE formation was stimulated up to twentyfold by 5mM ibuprofen. Other identified products include 5,15-DiHETE, 8,15-DiHETE, and 12-HETE. This ibuprofen-induced activation of 15-HETE formation occurred even in the presence of 10% serum. When the effects of aspirin, indomethacin, and ibuprofen were compared in PMN leukocytes from six donors, ibuprofen caused an average ninefold stimulation of 15-lipoxygenase, whereas aspirin and indomethacin exhibited an average 150% and 200% enhancement, respectively. Results suggest that ibuprofen acts at the postphospholipase stage and may mimic an endogenous activator, initiate a physiologic activation process, or displace a naturally occurring inhibitor of the 15-lipoxygenase. The capacity of NSAIDs to activate the 15-lipoxygenation of arachidonic acid provides a novel mechanism for the stimulation of 15-HETE production, which may indirectly stimulate the generation of leukotrienes by tissue mast cells.

Anti-Inflammatory Agents↗