Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Inflammatory pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,351 records · Page 75Linked to original sources
PubMed2006

Piceatannol attenuates lipopolysaccharide-induced NF-kappaB activation and NF-kappaB-related proinflammatory mediators in BV2 microglia.

Proinflammatory mediators, such as prostaglandin E(2) (PGE(2)), nitric oxide (NO), and proinflammatory cytokines [interlukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha] play pivotal roles in brain injuries. Anti-inflammatory responses are associated with significant downregulation of these proinflammatory mediators following brain injury. In the present study, we investigated the effects of piceatannol (PIC) on the production of proinflammatory mediators in lipopolysaccharide (LPS)-stimulated BV2 microglia. PIC significantly inhibited the release of NO, PGE(2), and proinflammatory cytokines in a dose-dependent manner. PIC also attenuated the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 mRNA and protein levels. Moreover, PIC prevented NF-kappaB p65 nuclear translocation. Our data also indicate that PIC exhibits anti-inflammatory properties by suppressing the transcription of proinflammatory cytokine genes through the NF-kappaB signaling pathway. The anti-inflammatory properties of PIC may be useful for attenuating inflammatory diseases and LPS-stimulated microglial activation.

Animals↗
PubMed2004

Hh pathway expression in human gut tissues and in inflammatory gut diseases.

Sonic hedgehog (Shh) directs early gut patterning via epithelial-mesenchymal signaling and remains expressed in endoderm-derived tissues into the adult period. In human adult gut epithelium SHH/SHH expression is strongest in basal layers, which suggests that SHH may function in the maintenance of gut epithelial stem or progenitor cells. Recent publications suggest a role for aberrant SHH/SHH expression in gut epithelial neoplasias. We hypothesized that the regenerating gut epithelium in inflammatory gut disorders would show an upregulation of SHH/SHH signaling and this abnormal signal may explain the increased incidence of neoplasia in these diseases. Archived healthy gut and inflammatory gut diseased tissues were analyzed by RNA in situ hybridization and immunohistochemistry to describe location and levels of SHH signaling. We show that SHH/SHH and its receptor PTCH1/PTCH1 expression is restricted to the glandular epithelium of the gut, in an antiluminal pattern (strongest in basal layers and weak to absent in luminal epithelium). Inflammatory diseases of the gut show dramatic increases in epithelial SHH signaling. Expression increases in inflamed glandular epithelium (including metaplastic glandular epithelium), losing its radial (crypt-villous) polarity, and expression appears upregulated and present in all epithelial cells. We also describe strong SHH/SHH and PTCH1/PTCH1 expression in intraepithelial and mucosal inflammatory cells. We suggest that SHH signaling in inflammatory diseases of the gut acts to ensure stem cell restitution of damaged mucosal epithelium. However, such signaling may also present a risk for neoplastic transformation.

Gastrointestinal Tract↗
PubMed1998

Takayasu arteritis, Buerger disease and inflammatory abdominal aortic aneurysms: is there a common pathway in their pathogenesis?

Takayasu arteritis, Bueger disease and IAAA are non-specific vasculitis involving mainly large vessels, the etiology of which are all still in the mist. Our recent HLA analysis on Takayasu arteritis and Buerger disease revealed a close association with some HLA antigens which made us suppose the common pathological pathway to cause these morbid conditions. International survey on Takayasu arteritis also revealed cases involving abdominal aorta only (Type IV, International Classification) in Asian countries, very similar to clinical and pathological features of IAAA. These ongoing survey suggest the common mechanism in the pathophysiology of these morbid conditions.

Aortic Aneurysm, Abdominal↗
PubMed2004

Contribution of conjugated linoleic acid to the suppression of inflammatory responses through the regulation of the NF-kappaB pathway.

Data from a number of researchers have shown that conjugated linoleic acid (CLA) has some beneficial health activities in animal models. Because inflammatory responses are associated with pathophysiology of many diseases, the aim of this study is to explore the effect and mechanism of CLA in the regulation of lipopolysaccharide (LPS)-induced inflammatory responses in RAW 264.7 macrophages. The addition of increasing levels of CLA proportionally augmented the incorporation of CLA in cultures. CLA diminished LPS-induced mRNA and protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2) as well as subsequent production of nitric oxide and prostaglandin E(2), respectively. We further examined the effect of CLA on LPS-induced NF-kappaB activation by Western blot and the electrophoretic mobility shift assay. The addition of CLA at 200 microM significantly diminished LPS-induced protein expression of the cytoplasmic phosphorylated inhibitor kappaBalpha and nuclear p65 as well as NF-kappaB nuclear protein-DNA binding affinity. In conclusion, our data suggest that CLA may inhibit LPS-induced inflammatory events in RAW 264.7 macrophages and this inhibitory activity of CLA, at least in part, occurs through CLA modulating the NF-kappaB activation and therefore negatively regulating expression of inflammatory mediators.

Animals↗
PubMed2003

Persistent over-expression of specific CC class chemokines correlates with macrophage and T-cell recruitment in mdx skeletal muscle.

Prior studies and the efficacy of immunotherapies provide evidence that inflammation is mechanistic in pathogenesis of Duchenne muscular dystrophy. To identify putative pro-inflammatory mechanisms, we evaluated chemokine gene/protein expression patterns in skeletal muscle of mdx mice. By DNA microarray, reverse transcription-polymerase chain reaction, quantitative polymerase chain reaction, and immunoblotting, convergent evidence established the induction of six distinct CC class chemokine ligands in adult MDX: CCL2/MCP-1, CCL5/RANTES, CCL6/mu C10, CCL7/MCP-3, CCL8/MCP-2, and CCL9/MIP-1gamma. CCL receptors, CCR2, CCR1, and CCR5, also showed increased expression in mdx muscle. CCL2 and CCL6 were localized to both monocular cells and muscle fibers, suggesting that dystrophic muscle may contribute toward chemotaxis. Temporal patterns of CCL2 and CCL6 showed early induction and maintained expression in mdx limb muscle. These data raise the possibility that chemokine signaling pathways coordinate a spatially and temporally discrete immune response that may contribute toward muscular dystrophy. The chemokine pro-inflammatory pathways described here in mdx may represent new targets for treatment of Duchenne muscular dystrophy.

Animals↗
PubMed2000

Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C.

We have identified a mechanism, mediated by the epsilon isozyme of protein kinase C (PKCepsilon) in peripheral neurons, which may have a role in chronic inflammatory pain. Acute inflammation, produced by carrageenan injection in the rat hindpaw, produced mechanical hyperalgesia that resolved by 72 hr. However, for up to 3 weeks after carrageenan, injection of the inflammatory mediators prostaglandin E(2) or 5-hydroxytryptamine or of an adenosine A(2) agonist into the same site induced a markedly prolonged hyperalgesia (>24 hr compared with 5 hr or less in control rats not pretreated with carrageenan). A nonselective inhibitor of several PKC isozymes and a selective PKCepsilon inhibitor antagonized this prolonged hyperalgesic response equally. Acute carrageenan hyperalgesia could be inhibited by PKA or PKG antagonists. However, these antagonists did not inhibit development of the hypersensitivity to inflammatory mediators. Our findings indicate that different second messenger pathways underlie acute and prolonged inflammatory pain.

Adenosine↗
PubMed1988

Local anti-inflammatory activities of tixocortol 21-pivalate, inhibition of prostaglandins and leukotrienes synthesis, in carrageenin-induced pleurisy. Reversion of effects by RU 486.

Since a direct effect of tixocortol pivalate (TP) has been described on cyclooxygenase pathway, local anti-inflammatory activities of some 21 thiol derivatives of steroids were investigated on the carrageenin-induced pleurisy model in comparison with dexamethasone (Dex) or other anti-inflammatory drugs. LTC4/D4 contents in pleural fluid were assayed by RIA as well as PGE2 levels to characterize the effects on arachidonate pathways. After oral administration, TP was inactive up to 1 g/kg on exudate volume and leukocyte migration as expected for this strict local anti-inflammatory steroid contrary to Dex (ID50 = 0.05-0.41 mg/kg). When administered locally, TP and tixocortol (T) exerted a dose dependent inhibitory activity on exudate volume (ID30 = 12.4 micrograms or 13.1 micrograms/pleural cavity) and leukocyte count (ID30 = 83 or 230 micrograms); in the same conditions. Dex was more active (ID30 = 0.7 and 2.6 micrograms). All these steroids decreased PGE2 and LTC4/D4 contents in exudate fluids, respectively TP (50 micrograms/pleural cavity) by 28 and 63%; T (100 micrograms) by 33 and 31%; Dex (5 micrograms) by 43 and 40%. Local co-administration of RU 486 (50 micrograms) with either TP, T or Dex reversed the anti-inflammatory effects of all steroids, indicating in these conditions a local activity through glucosteroid receptor occupancy.

Administration, Topical↗
PubMed2002

Leishmania major activates IL-1 alpha expression in macrophages through a MyD88-dependent pathway.

Leishmania species present unusual challenges to the immune system with their capacity to downregulate inflammatory responses as well as their ability to live within macrophages. Although toll-like receptor (TLR) pathways have been implicated in the recognition of several classes of pro-inflammatory microbes, it is not known if pathogens with anti-inflammatory properties activate the host response through this family of proteins. In this study, Leishmania major stimulation of cytokine promoter-luciferase reporter constructs was examined in transfected macrophages to detect early signs of cellular activation. L. major selectively activated the promoter region of IL-1 alpha, but not IL-6, IL-8, IL-10, or an NF-kappa B reporter. IL-1 alpha mRNA expression was also stimulated by L. major, although at lower levels than lipopolysacharide-stimulated macrophages. No IL-1 alpha protein was detectable in stimulated cell lysates or culture supernatants. Transfection of macrophages with a dominant-negative version of myeloid differentiation factor 88 (MyD88), an adaptor protein which interacts with TLRs, inhibited activation of the IL-1 alpha promoter. Furthermore, stimulation of IL-1 alpha RNA expression by L. major was inhibited in peritoneal macrophages from MyD88-/- as compared to MyD88+/+ mice. These observations indicate that L. major stimulates IL-1 alpha promoter activity and mRNA expression in macrophages through MyD88-dependent pathways. However, additional anti-inflammatory pathways must also be activated which downregulate transcription and ultimately inhibit translation of the IL-1 alpha protein. Examination of promoter activation is a powerful tool for understanding the early events in macrophage activation for anti-inflammatory pathogens such as Leishmania that have mechanisms to downregulate transcription and translation.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Recombinant TNF-alpha mediated regulation of the I kappa B-alpha/NF-kappa B signaling pathway: evidence for the enhancement of pro- and anti-inflammatory cytokines in alveolar epithelial cells.

The signaling transduction mechanism mediated by tumor necrosis factor-alpha (TNF-alpha) in the alveolar epithelium is not well characterized. It was subsequently hypothesized that recombinant murine TNF-alpha (rmTNF-alpha) selectively regulates the inhibitory kappa B (I kappa B-alpha)/nuclear factor-kappa B (NF-kappa B) pathway and interferes with the endogenous biosynthesis of pro-inflammatory (stimulatory) and anti-inflammatory (inhibitory) cytokines. The cytokine rmTNF-alpha induced, in a time- and dose-dependent manner, the degradation of I kappa B-alpha within the cytosolic compartment, an effect associated with up-regulating its phosphorylation. This allowed the biphasic regulation of selective NF-kappa B subunit nuclear translocation, thereby mediating a dual excitatory mechanism on NF-kappa B activation. The immunoregulatory effect of rmTNF-alpha was associated with a time-dependent induction of pro-inflammatory [interleukin (IL)-1 beta, IL-6 and TNF-alpha] and anti-inflammatory (IL-10) cytokine biosynthesis. These results indicate a novel involvement of an I kappa B-alpha/NF-kappa B-sensitive pathway mediating the effect of TNF-alpha, which is associated with an autocrine, endogenous mechanism mediating the regulation of cytokine signaling.

Animals↗
PubMed2002

Global genomic analysis of AlgU (sigma(E))-dependent promoters (sigmulon) in Pseudomonas aeruginosa and implications for inflammatory processes in cystic fibrosis.

The conversion of Pseudomonas aeruginosa to the mucoid phenotype coincides with the establishment of chronic respiratory infections in cystic fibrosis (CF). A major pathway of conversion to mucoidy in clinical strains of P. aeruginosa is dependent upon activation of the alternative sigma factor AlgU (P. aeruginosa sigma(E)). Here we initiated studies of AlgU-dependent global expression patterns in P. aeruginosa in order to assess whether additional genes, other than those involved in the production of the mucoid exopolysaccharide alginate, are turned on during conversion to mucoidy. Using genomic information and the consensus AlgU promoter sequence, we identified 35 potential AlgU (sigma(E)) promoter sites on the P. aeruginosa chromosome. Each candidate promoter was individually tested by reverse transcription and mRNA 5'-end mapping using RNA isolated from algU(+) and algU::Tc(r) mutant cells. A total of 10 new AlgU-dependent promoters were identified, and the corresponding mRNA start sites were mapped. Two of the 10 newly identified AlgU promoters were upstream of predicted lipoprotein genes. Since bacterial lipoproteins have been implicated as inducers of inflammatory pathways, we tested whether lipopeptides corresponding to the products of the newly identified AlgU-dependent lipoprotein genes, lptA and lptB, had proinflammatory activity. In human peripheral blood monocyte-derived macrophages the peptides caused production of interleukin-8, a proinflammatory chemokine typically present at excessively high levels in the CF lung. Our studies show how genomic information can be used to uncover on a global scale the genes controlled by a given sigma factor (collectively termed here sigmulon) using conventional molecular tools. In addition, our data suggest the existence of a previously unknown connection between conversion to mucoidy and expression of lipoproteins with potential proinflammatory activity. This link may be of significance for infections and inflammatory processes in CF.

Amino Acid Sequence↗
PubMed1998

Phospholipase A2 activation and increases in specific prostaglandins in the oxidatively stressed 14CoS/14CoS mouse hepatocyte line.

This laboratory has previously shown that increases in the expression of several genes in SV40-transformed hepatocyte cultures derived from the untreated newborn c14CoS/c14CoS mouse, and in newborn mouse liver--when compared with the cch/cch wild-type--are associated with enhanced levels of reactive oxygenated metabolites (ROMs) and reduced glutathione (GSH). We show here that, in contrast to the ch/ch wild-type levels, the oxidatively stressed 14CoS/14CoS liver cell line displays 2- to 5-fold increases in 1) phospholipase A2 (PLA2) enzyme activity, 2) Ca2+ dependent Group II secreted PLA2 mRNA levels, 3) arachidonic acid release, and 4) arachidonic acid metabolites co-eluting with prostaglandins D2, E2, and F2 alpha. These findings suggest that the cyclooxygenase-2 (COX2) pathway, and possible involvement of the "inflammatory" and/or "acute phase response" signal transduction pathways, might be activated during the endogenous ROM-mediated oxidative stress response in 14CoS/14CoS cells.

Animals↗
PubMed1996

Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis.

Increased cyclic AMP-phosphodiesterase activity in peripheral blood leukocytes is associated with the immune and inflammatory hyperreactivity that characterizes atopic dermatitis. Atopic phosphodiesterase has high sensitivity to a variety of enzyme inhibitors, suggesting an increased therapeutic advantage. The objective of this study was to use in vitro assays to identify a potent phosphodiesterase inhibitor and then to investigate its effectiveness in treating atopic dermatitis. Leukocyte enzyme activity was measured by radioenzyme assay, whereas prostaglandin E2 and interleukins 10 (IL-10) and 4 (IL-4) were measured in 24-h culture supernatants of mononuclear leukocytes by immunoassays. The effect of a topical phosphodiesterase inhibitor on atopic dermatitis lesional skin was assessed by double-blind, paired comparisons of active drug and placebo ointments applied to symmetrically involved sites over a 28-d period. Using in vitro, assays, we demonstrated the ability of selective high-potency phosphodiesterase inhibitors to reduce prostaglandin E2, IL-10, and IL-4 production in atopic mononuclear leukocyte cultures. We selected the Type 4 phosphodiesterase inhibitor, CP80,633, based on its inhibitory potency, for clinical testing by topical, bilateral paired comparisons in 20 patients with atopic dermatitis and demonstrated significant reductions of all inflammatory parameters. Phosphodiesterase inhibitors modulate several pathways contributing to the exaggerated immune and inflammatory responses, which characterize atopic dermatitis. This in vivo demonstration of anti-inflammatory efficacy may provide a useful alternative to the over-reliance on corticosteroid therapy in atopic disease.

Administration, Topical↗
PubMed2000

Glycyrrhizin inhibits the lytic pathway of complement--possible mechanism of its anti-inflammatory effect on liver cells in viral hepatitis.

Glycyrrhizin, an aqueous extract of licorice root, has anti-inflammatory activity and has been used for the treatment of chronic viral hepatitis. In the present study we describe the mechanism by which glycyrrhizin inhibits complement. Glycyrrhizin inhibited the cytolytic activity of complement via the activation of both the classical and alternative pathways, while it had no effect on immune adherence, suggesting that it blocks C5 or a later stage of the complement cascade. Further analysis revealed that glycyrrhizin inhibits the lytic pathway in which the membrane attack complex (MAC) is formed. This mechanism suggests that glycyrrhizin may prevent tissue injury caused by MAC not only in chronic hepatitis but in many autoimmune and inflammatory diseases.

Animals↗
PubMed2002

Airway hyperresponsiveness: using bronchial challenge tests in research and management of asthma.

Bronchial challenge tests have been standardized in detail during the past two decades. They are providing relevant pathophysiological and clinical information about patients with asthma or chronic obstructive pulmonary disease (COPD), by allowing the measurement of the degree of airway hyperresponsiveness, which includes an increased sensitivity as well as increased maximal response to bronchoconstrictor stimuli. There are various types of challenges, to which the responses are not interchangeable. Responses to so-called "indirect" challenges are largely dependent on the state of activation of inflammatory or resident cells within the airways, and the state of activation can vary rapidly, either spontaneously or through intervention. Responses to "direct" challenges are dependent on less variable, rather chronic features of airways inflammation or remodeling. Bronchoprovocation tests provide integrated information about multiple pathophysiological pathways within the airway. This is in contrast to the measurements of cells, mediators, or cytokines in biological fluids, which provide only very specific information on selected inflammatory pathways. It has recently been shown that the outcome of asthma can substantially be improved when long-term treatment is not only guided by symptoms and lung function, but also by the degree of airway hyperresponsiveness to direct stimuli. Taken together, current data warrant a broader usage of bronchoprovocation tests in the research as well as clinical management of asthma and COPD. In asthma, it allows selective, individually targeted therapy of the patient as opposed to the currently recommended regimens that are (increasingly) unselective in their approach. The potential benefits of monitoring other phenotypic disease markers is currently under investigation.

Anti-Asthmatic Agents↗
PubMed2003

How nerve growth factor drives physiological and inflammatory expressions of acid-sensing ion channel 3 in sensory neurons.

Nerve growth factor (NGF) is a key element of inflammatory pain. It induces hyperalgesia by up-regulating the transcription of genes encoding receptors, ion channels, and neuropeptides. Acid-sensing ion channel 3 (ASIC3), a depolarizing sodium channel gated by protons during tissue acidosis, is specifically expressed in sensory neurons. It has been associated to cardiac ischemic and inflammatory pains. We previously showed that low endogenous NGF was responsible for ASIC3 basal expression and high NGF during inflammation increased ASIC3 expression parallely to the development of neuron hyperexcitability associated with hyperalgesia. NGF is known to activate numerous signaling pathways through trkA and p75 receptors. We now show that (i). NGF controls ASIC3 basal expression through constitutive activation of a trkA/phospholipase C/protein kinase C pathway, (ii). high inflammatory-like NGF induces ASIC3 overexpression through a trkA/JNK/p38MAPK pathway and a p75-dependent mechanism as a transcriptional switch, and (iii). NGF acts through AP1 response elements in ASIC3 encoding gene promoter. These new data indicate potential targets that could be used to develop new treatments against inflammatory pain.

Acid Sensing Ion Channels↗
PubMed2005

Alcohol and pancreatic cancer.

Findings obtained from numerous prospective cohort and case-control studies on alcohol consumption and pancreatic cancer risk have been inconsistent, with many confounding variables present in various investigations. However, heavy alcohol consumption has been known to be a major cause of chronic pancreatitis and a risk factor for type 2 diabetes mellitus, both of which are linked to pancreatic cancer. It has been established that an extensive normal interaction exists between the exocrine and endocrine pancreas, as well as in inflammatory processes and carcinogenesis. Alcohol and its metabolites (acetaldehyde and fatty acid ethyl esters) can alter metabolic pathways involved in the inflammatory response and carcinogenesis, and they are mediated by one or more of the following mechanisms: (1) premature activation of zymogens; (2) induction of the inflammatory response through activation of nuclear transcription factors, including nuclear factor-kappa and activation protein 1; (3) increased production of reactive oxygen species, resulting in oxidative DNA damage and altered effect of dietary antioxidants; (4) activation of pancreatic stellate cells, which leads to fibrosis; (5) gene mutation in enzymes related to cytochrome P450, glutathione S-transferase, aldehyde dehydrogenase, cationic trypsinogen, and pancreatic secretory trypsin inhibitor; (6) synergistic effects of ethanol and tobacco carcinogen on NNK [nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] metabolism; and (7) dysregulation of proliferation and apoptosis. These various metabolic effects of alcohol can lead to or interact with other risk factors (genetic, dietary, environmental, and lifestyle factors) that result in acute and chronic pancreatitis and diabetes mellitus and, ultimately, affect the multistep process of carcinogenesis toward the development of pancreatic cancer.

Alcohol Drinking↗