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At least 1,675 records · Page 93Linked to original sources
PubMed2003

Role of the phosphatidylinositol 3 kinase-Akt pathway in the regulation of IL-10 and IL-12 by Porphyromonas gingivalis lipopolysaccharide.

Stimulation of the APC by Porphyromonas gingivalis LPS has been shown to result in the production of certain pro- and anti-inflammatory cytokines. However, the signaling pathways that regulate these processes are currently unknown. In the present study, the role of the phosphatidylinositol 3 kinase (PI3K)-Akt pathway in regulating P. gingivalis LPS-induced production of IL-10, IL-12 p40, and IL-12 p70 by human monocytes was investigated. P. gingivalis LPS selectively activates the PI3K-Akt pathway via Toll-like receptor 2, and inhibition of this pathway results in an abrogation of extracellular signal-regulated kinase 1/2 phosphorylation, whereas the activation of p38 and c-Jun N-terminal kinase 1/2 kinases were unaffected. Analysis of cytokine production following stimulation of monocytes with P. gingivalis LPS revealed that inhibition of the PI3K pathway differentially regulated IL-10 and IL-12 synthesis. IL-10 production was suppressed, whereas IL-12 levels were enhanced. Inhibition of P. gingivalis LPS-mediated activation of the PI3K-Akt pathway resulted in a pronounced augmentation of NF-kappaB p65 that was independent of IkappaB-alpha degradation. Furthermore, the ability of the PI3K-Akt pathway to modulate IL-10 and IL-12 production appears to be mediated by the selective suppression of extracellular signal-regulated kinase 1/2 activity, as the MEK1 inhibitor PD98059 closely mimicked the effects of wortmannin and LY294002 to differentially regulate IL-10 and IL-12 production by P. gingivalis LPS-stimulated monocytes. These studies provide new insight into how engagement of the PI3K-Akt pathway by P. gingivalis LPS affects the induction of key immunoregulatory cytokines that control both qualitative and quantitative aspects of innate and adaptive immunity.

Cells, Cultured↗
PubMed2004

5'-methylthioadenosine modulates the inflammatory response to endotoxin in mice and in rat hepatocytes.

5'-methylthioadenosine (MTA) is a nucleoside generated from S-adenosylmethionine (AdoMet) during polyamine synthesis. Recent evidence indicates that AdoMet modulates in vivo the production of inflammatory mediators. We have evaluated the anti-inflammatory properties of MTA in bacterial lipopolysaccharide (LPS) challenged mice, murine macrophage RAW 264.7 cells, and isolated rat hepatocytes treated with pro-inflammatory cytokines. MTA administration completely prevented LPS-induced lethality. The life-sparing effect of MTA was accompanied by the suppression of circulating tumor necrosis factor-alpha (TNF-alpha), inducible NO synthase (iNOS) expression, and by the stimulation of IL-10 synthesis. These responses to MTA were also observed in LPS-treated RAW 264.7 cells. MTA prevented the transcriptional activation of iNOS by pro-inflammatory cytokines in isolated hepatocytes, and the induction of cyclooxygenase 2 (COX2) in RAW 264.7 cells. MTA inhibited the activation of p38 mitogen-activated protein kinase (MAPK), c-jun phosphorylation, inhibitor kappa B alpha (IkappaBalpha) degradation, and nuclear factor kappaB (NFkappaB) activation, all of which are signaling pathways related to the generation of inflammatory mediators. These effects were independent of the metabolic conversion of MTA into AdoMet and the potential interaction of MTA with the cAMP signaling pathway, central to the anti-inflammatory actions of its structural analog adenosine. In conclusion, these observations demonstrate novel immunomodulatory properties for MTA that may be of value in the management of inflammatory diseases.

Animals↗
PubMed2004

Molecular mechanisms of anti-inflammatory action of erythromycin in human bronchial epithelial cells: possible role in the signaling pathway that regulates nuclear factor-kappaB activation.

Long-term macrolide therapy has been proven to improve survival in patients with diffuse panbronchiolitis. Although its mechanisms remain unknown, previous studies have suggested the effects of macrolide might be anti-inflammatory rather than antibacterial. To elucidate the molecular mechanisms of its action, we studied here the effects of erythromycin (EM) and its new derivative, EM703, which shows no antibacterial action, on the activation of the transcription factor nuclear factor-kappaB (NF-kappaB) in human bronchial epithelial cells. Western blotting analysis showed that EM did not inhibit the degradation of IkappaBalpha, suggesting the molecular target for EM was not the dissociation of NF-kappaB from IkappaB. An electrophoretic mobility shift assay showed that EM did not interrupt the NF-kappaB DNA-binding activity in the nucleus under the conditions tested. Moreover, not only EM but also EM703 suppressed the activation of NF-kappaB and the production of interleukin-8, demonstrating that the anti-inflammatory action of the macrolide is independent of its antibacterial activity. Taken together, these data suggest EM has an anti-inflammatory action, presumably via an interaction with the NF-kappaB signaling pathway in the downstream of the dissociation from IkappaB, resulting in the inhibition of NF-kappaB.

Anti-Bacterial Agents↗
PubMed2005

High glucose-induced human umbilical vein endothelial cell hyperpermeability is dependent on protein kinase C activation and independent of the Ca2+-nitric oxide signalling pathway.

1. Endothelial barrier dysfunction plays a pivotal role in the pathogenesis of diabetic vascular complications. The precise molecular mechanisms by which hyperglycaemia causes the increased permeability in endothelial cells are not yet well understood. In the present study, we investigated whether high concentrations of glucose induce endothelial permeability through the activation of protein kinase C (PKC) and/or the calcium-nitric oxide (NO) signalling pathway in human umbilical vein endothelial cells (HUVEC). 2. Endothelial permeability was measured by albumin diffusion across endothelial monolayers under the stimuli of high glucose (HG; 20 mmol/L), 100 nmol/L phorbol-myristate-acetate (PMA) or 100 nmol/L histamine. The intracellular calcium concentration ([Ca2+]i) was detected in HUVEC using the fluorescent probe fura-2 AM. The effects of PKC inhibitors (LY379196 and hypocrellin A) and the NO synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA) on endothelial permeability and [Ca2+]i were determined. 3. High glucose and PMA increased endothelial permeability associated with decreased [Ca2+]i, whereas histamine triggered significant increases in endothelial permeability, accompanied by increases in [Ca2+]i in HUVEC. Hypocrellin A (HA) and LY379196 reversed both HG- and histamine-induced endothelial permeability. The NOS inhibitor L-NMMA only abolished histamine- and not HG-induced endothelial permeability. Neither LY379196, HA nor L-NMMA had any significant effects on alterations in [Ca2+]i caused by HG and histamine. 4. These results indicate that increased endothelial permeability in HUVEC induced by HG is dependent on PKC activity and is independent of the [Ca2+]i-NO pathway. Increased endothelial permeability due to other inflammatory factors, such as histamine, may also be mediated by the PKC pathway. Thus, PKC inhibitors would be a potential therapeutic approach to endothelial dysfunction induced by hyperglycaemia, as well as other inflammatory factors, in diabetes.

Calcium Signaling↗
PubMed2001

Signal transduction pathways in sarcoma as targets for therapeutic intervention.

Investigations into the molecular alterations in sarcomas have made substantial progress during the past decade. Classical linkage analysis and the direct sequencing of chromosomal translocation fusions have identified candidate genes in many different sarcomas. A large group of these genes participate in signal transduction pathways and represent potential sites of disease intervention with targeted therapies. This review will discuss five types of sarcoma that display aberrant tyrosine kinase pathway signaling: gastrointestinal stromal tumor, inflammatory myofibroblastic tumor, congenital fibrosarcoma and mesoblastic nephroma, dermatofibrosarcoma protuberans, and desmoplastic small round cell tumor; one sarcoma predisposition syndrome with specific dysregulation of the ras pathway--neurofibromatosis--will also be discussed.

Antineoplastic Agents↗
PubMed1995

Indicators of oxidative tissue damage and inflammatory activity in epiretinal membranes of proliferative diabetic retinopathy, proliferative vitreoretinopathy and macular pucker.

PURPOSE: To evaluate whether oxidative tissue damage and inflammatory reactions occur in epiretinal membranes of eyes suffering from proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR), and macular pucker (MP). METHODS: Epiretinal membranes were removed during surgery and frozen at -80 degrees C (PDR, n = 26; PVR, n = 24; MP, n = 15), and oxidative tissue damage and inflammatory activity (MPO) of the membrane tissue were determined. The values are expressed as means of thiobarbituric acid-reactive substances (TBARS, nmol/mg) and MPO (units/mg). RESULTS: Both TBARS and MPO activity were significantly elevated (P < 0.05) in membranes of eyes suffering from PVR and PDR compared to MP. The myeloperoxidase activity in PDR membranes was significantly increased (P < 0.05) compared to PVR. CONCLUSIONS: Inflammatory cells and oxidative metabolites lead to oxidative reactions in PDR and PVR. The proliferation of membrane tissue may be enhanced through products of the lipoxygenase pathway, which is active in inflammatory cells and leads to oxidative tissue damage. Chemoattraction of leukocytes by oxidative metabolites renders the process self-progagating. Since patients suffering from MP have an intact vitreous body with an intact antioxidative system, this reaction occurs to a lesser degree, resulting in less membrane-growth activity. The cell-growth-enhancing properties of inflammatory cells should be further investigated in PDR and PVR with regard to new therapeutic interventions.

Cell Membrane↗
PubMed2005

Effects of the active metabolite of leflunomide, A77 1726, on cytokine release and the MAPK signalling pathway in human rheumatoid arthritis synoviocytes.

Inflammatory cytokines or soluble factors are essential in the pathogenesis of rheumatoid arthritis (RA). Leflunomide is an effective disease modifying antirheumatic drug (DMARD) in RA. The objective of the present study was to evaluate for the first time the effects of A77 1726 on cytokine (interleukin (IL)-8, IL-10, IL-11 secretion and tumor necrosis factor-alpha soluble receptor I (sTNFRI)) shedding in human RA fibroblast-like synoviocytes (FLS). At 100 microM, we observed an increase in IL-10 secretion, a decrease in IL-11 release and no effect on sTNFRI shedding and IL-8 secretion in IL-1beta-stimulated human RA FLS. Furthermore, at this dose, our results also confirmed that A77 1726 decreased IL-6 and prostaglandin E2 (PGE2) synthesis while it increased IL-1 receptor antagonist secretion (IL-1Ra). The mitogen-activated protein kinases (MAPKs) represent an attractive target for RA because they can regulate cytokine expression. At 100 microM, the effect of A77 1726 on IL-10 and IL-11 secretion seemed to be associated with the status of p38 MAPK activation. Our results confirmed the immunoregulatory action of leflunomide in the cytokine network involved in RA pathogenesis. It could shift the balance from cytokine mediated inflammation to cytokine directed inhibition of the inflammatory process.

Active Transport, Cell Nucleus↗
PubMed2004

Mefenamic acid-induced apoptosis in human liver cancer cell-lines through caspase-3 pathway.

Non-steroidal anti-inflammatory drugs (NSAIDs) have anti-proliferative effects and induce apoptosis in colon and other cancers. In the present study, we report that mefenamic acid (MEF), a member of NSAIDs, has an inhibitory effect on a proliferation of liver cancer cells. We used Chang and Huh-7 cells as human liver cancer cells. MEF-treated Huh-7 and Chang cells displayed apoptotic morphological changes and the portion of cells in sub G1 was increased 3-fold and 6-fold, respectively, at a 200 microM concentration. We also show an MEF-enhanced binding of annexin V to cells and an increased activity of caspase-3 to cleave PARP-1 and caspase itself. The inhibitor of caspase-3 blocked PARP-1 cleavage activity and protected against MEF-induced apoptotic cell death. These results indicate that MEF induces apoptosis in human liver cancer cells.

Annexin A5↗
PubMed2006

Characterization of the pro-inflammatory signaling induced by protein acetylation in microglia.

Protein acetylation regulates the extent of inflammatory responses and disturbances in protein acetylation have been proposed to play an important role in inflammatory and neurodegenerative diseases. We have recently observed that histone deacetylase inhibitors, such as trichostatin A (TSA) and SAHA, strongly potentiate the LPS induced inflammatory response in several rat and mouse inflammatory models. Our aim here was to characterise pro-inflammatory signaling mediated via increased protein acetylation and protein phosphorylation in microglial N9 cells. First we observed that TSA induced pro-inflammatory response was independent of the different Toll-like receptors activated, since LPS, flagellin and unmethylated CpG oligonucleotides, equally potentiated IL-6 secretion from N9 microglia. Next we compared the protein acetylation induced potentiation to that induced by okadaic acid, a well-known inducer of pro-inflammatory responses. The time scale of the IL-6 responses showed that the effects of okadaic acid were clearly early-response effects appearing as soon as 6h after exposure, whereas TSA evoked a significant inhibition in IL-6 secretion up to 12h but after that it induced an exponential increase in cytokine and nitric oxide production up to 24h. It seems that okadaic acid induces an early moderate response and TSA a late but exponential potentiation of microglial inflammatory responses. The pro-inflammatory responses of TSA and okadaic acid were both dependent on NF-kappaB signaling but independent on the DNA-binding capacity of nuclear NF-kappaB complexes. Interestingly, we observed that the transactivation of the NF-kappaB-Luc reporter gene was clearly activated during TSA induced pro-inflammatory potentiation. Our studies imply that the potentiation of the inflammatory response by increased acetylation is due to the enhancement of transactivation of NF-kappaB driven inflammatory genes. Our studies on signaling pathways revealed that PI3K inhibitors LY294002 and Wortmannin blocked the TSA induced pro-inflammatory response but surprisingly did not affect the okadaic acid induced response. Furthermore, LY294002 did not inhibit DNA-binding activity of NF-kappaB but still inhibited NF-kappaB-Luc reporter gene transactivation. These results indicate that PI 3-kinase regulates the transactivation efficiency of NF-kappaB-dependent transcription rather than transduction of NF-kappaB signaling.

Acetylation↗
PubMed2005

Piceatannol upregulates endothelial heme oxygenase-1 expression via novel protein kinase C and tyrosine kinase pathways.

Piceatannol is an anti-inflammatory and anti-proliferative plant-derived stilbene. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme to activate by various phytochemicals. In this study, we examined the ability of piceatannol to upregulate HO-1 expression in endothelial cells. We found piceatannol at micromolar (10-50 microM) concentrations dramatically increased HO-1 protein levels in a time-dependent manner. Piceatannol was similarly potent in the induction of HO-1 as hemin, arsenate, and 15d-PGJ2, and was more potent than some other phytochemicals including curcumin, EGCG, baicalein, and quercetin. In contrast, the similar chemical structure compounds, trans-stilbene, stilbene oxide, and resveratrol had no HO-1-inducing effects, suggesting a critical role for the hydroxyl groups in HO-1 induction. No cytotoxicity and superoxide production was observed after 10-50 microM piceatannol treatments. Piceatannol-mediated HO-1 induction was abrogated in the presence of N-acetylcysteine and glutathione, but not by other antioxidants. Induction of HO-1 by piceatannol was further enhanced by using buthionine sulfoximine. In addition, we determined that tyrosine kinase was involved in the induction of HO-1 by using tyrosine kinase inhibitors, herbimycin A, erbstatin, and genistein; in contrast, no significant changes in the pretreatment of PI3 kinase or MAP kinase inhibitors was determined. HO-1 induction was blocked by the protein kinase C inhibitors calphostin C, rottlerin, and long PMA pretreatment, whereas conventional PKC inhibitors, Go6976, and Ca2+ chelator BAPTA/AM, had no effect. Elevated HO-1 protein levels were associated with the inhibition of tumor necrosis factor-alpha (TNFalpha)-induced intercellular adhesion molecule-1 (ICAM-1) expression. Treating ECs with zinc protoporphyrin, an HO-1 inhibito blocked the anti-inflammatory effect of piceatannol. In summary, this study identified piceatannol as a novel phytochemical inducer of HO-1 expression and identified the mechanisms involved in this process.

Animals↗
PubMed1998

IL-10 inhibits macrophage activation and proliferation by distinct signaling mechanisms: evidence for Stat3-dependent and -independent pathways.

Interleukin-10 (IL-10) limits inflammatory responses by inhibiting macrophage activation. In macrophages, IL-10 activates Stat1 and Stat3. We characterized IL-10 responses of the J774 mouse macrophage cell line, and of J774 cells expressing wild-type hIL-10R, mutant hIL-10R lacking two membrane-distal tyrosines involved in recruitment of Stat3 (hIL-10R-TyrFF), a truncated Stat3 (DeltaStat3) which acts as a dominant negative, or an inducibly active Stat3-gyraseB chimera (Stat3-GyrB). A neutralizing anti-mIL-10R monoclonal antibody was generated to block the function of endogenous mIL-10R. IL-10 inhibited proliferation of J774 cells and of normal bone marrow-derived macrophages, but not J774 cells expressing hIL-10RTyrFF. Dimerization of Stat3-GyrB by coumermycin mimicked the effect of IL-10, and expression of DeltaStat3 blocked the anti-proliferative activity of IL-10. For macrophage de-activation responses, hIL10R-TyrFF could not mediate inhibition of lipopolysaccharide-induced TNFalpha, IL-1beta or CD86 expression, while DeltaStat3 did not interfere detectably with these IL-10 responses. Thus signals mediating both anti-proliferative and macrophage de-activation responses to IL-10 require the two membrane-distal tyrosines of IL-10R, but Stat3 appears to function only in the anti-proliferative response.

Animals↗
PubMed2003

Contribution of reactive oxygen species to cartilage degradation in rheumatic diseases: molecular pathways, diagnosis and potential therapeutic strategies.

Inflammatory joint diseases are of considerable socio-economic significance. However, mechanisms of cartilage destruction are so far only poorly understood. This review is dedicated to reactive oxygen species (ROS) like superoxide anion radicals, hydrogen peroxide, singlet oxygen, hypochlorous acid, hydroxyl radicals and nitric oxide that are generated under inflammatory conditions and also to their potential contribution to cartilage degradation. First, the relevance of rheumatic diseases and potential mechanisms of cartilage degradation are discussed in this review, followed by the description of the chemical constituents and the molecular architecture of articular cartilage as well as the different cell types that play a role in inflammation and cartilage destruction. Methods of the assessment of cartilage degeneration are also shortly discussed. In the main chapter of this review the characteristics of individual ROS, their generation under in vivo conditions as well as their reactivities with individual cartilage components are discussed. Because of the low selectivity of ROS, useful "markers" of cartilage degradation allowing the differentiation of effects induced by individual ROS are also discussed. In the last chapter current therapeutic concepts of the treatment of rheumatic diseases are reviewed. The recently developed "anti-TNF-alpha" therapy that is primarily directed against neutrophilic granulocytes that are powerful sources of ROS and, therefore, important mediators of joint degeneration are emphasised.

Animals↗
PubMed2002

C3 adsorbed to a polymer surface can form an initiating alternative pathway convertase.

Contact between blood and a biomaterial surface induces an immediate complement-mediated inflammatory response. Under these conditions, the alternative pathway of complement is often initiated and amplified on the biomaterial surface. Adsorption of a protein such as C3 to a polymer surface induces conformational changes in the protein. Based on the expression on adsorbed C3 of conformational neoepitopes specific for bound C3 fragments, we have hypothesized that adsorbed C3 is able to bind factor B and form a functional C3,Bb convertase. Using a quartz crystal microbalance to monitor binding of proteins to a polymer surface, we have demonstrated that a functional C3-containing alternative pathway convertase can be formed, in particular, in the presence of properdin. These data indicate that adsorption of C3 induces conformational changes that turn C3 into a C3b-like molecule that is able to participate in the functioning of the alternative convertase, and they suggest a new mechanism for complement activation on a biomaterial surface.

Adsorption↗
PubMed2006

Targeted immunomodulation of the NF-kappaB pathway in airway epithelium impacts host defense against Pseudomonas aeruginosa.

We investigated the impact of inflammatory signaling in airway epithelial cells on host defense against Pseudomonas aeruginosa, a major cause of nosocomial pneumonia. In mice, airway instillation of P. aeruginosa resulted in NF-kappaB activation in the lungs that was primarily localized to the bronchial epithelium at 4 h, but was present in a variety of cell types by 24 h. We modulated NF-kappaB activity in airway epithelium by intratracheal delivery of adenoviral vectors expressing RelA (AdRelA) or a dominant inhibitor of NF-kappaB before P. aeruginosa infection. Bacterial clearance was enhanced by up-regulation of NF-kappaB activity following AdRelA administration and was impaired by treatment with a dominant inhibitor of NF-kappaB. The TNF-alpha concentration in lung lavage was increased by AdRelA treatment and beneficial effects of NF-kappaB up-regulation were abrogated in TNF-alpha-deficient mice. In contrast, NF-kappaB inhibition reduced MIP-2 expression and neutrophil influx following P. aeruginosa infection. Therefore, inflammatory signaling through the NF-kappaB pathway in airway epithelial cells critically regulates the innate immune response to P. aeruginosa.

Animals↗
PubMed1992

Anticomplementary activity of boswellic acids--an inhibitor of C3-convertase of the classical complement pathway.

Boswellic acids (BA), an anti-inflammatory and anti-arthritic principle/s of Boswellia serrata, were found to possess anticomplementary activity. It inhibits the in vitro immunohaemolysis of antibody-coated sheep erythrocytes by pooled guinea-pig serum. The reduced immunohaemolysis was found to be due to inhibition of C3-convertase of the classical complement pathway. The threshold concentration for inhibiting C3-convertase was found to be 100 micrograms. However, higher concentrations of BA showed constant inhibitory effects on immunohaemolysis. BA also exhibited weak inhibitory effects on individual components of the complement system. In vivo administration of BA also showed the inhibitory effect on guinea-pig serum.

Animals↗
PubMed1999

Constitutive activation of an epithelial signal transducer and activator of transcription (STAT) pathway in asthma.

Cytokine effects on immunity and inflammation often depend on the transcription factors termed signal transducers and activators of transcription (STATs), so STAT signaling pathways are candidates for influencing inflammatory disease. We reasoned that selective IFN responsiveness of the first STAT family member (Stat1) and Stat1-dependent immune-response genes such as intercellular adhesion molecule-1 (ICAM-1), IFN regulatory factor-1 (IRF-1), and Stat1 itself in airway epithelial cells provides a basis for detecting cytokine signaling abnormalities in inflammatory airway disease. On the basis of nuclear localization and phosphorylation, we found that epithelial Stat1 (but not other control transcription factors) was invariably activated in asthmatic compared with normal control or chronic bronchitis subjects. Furthermore, epithelial levels of activated Stat1 correlated with levels of expression for epithelial ICAM-1, IRF-1, and Stat1, and in turn, ICAM-1 levels correlated with T-cell accumulation in tissue. However, only low levels of IFN-gamma or IFN-gamma-producing cells were detected in airway tissue in all subjects. The results therefore provide initial evidence linking abnormal behavior of STAT pathways for cytokine signaling to the development of an inflammatory disease. In that context, the results also change the current scheme for asthma pathogenesis to one that must include a localized gain in transcriptional signal ordinarily used for a T helper 1-type cytokine (IFN-gamma) in combination with allergy-driven overproduction of T helper 2-type cytokines.

Asthma↗
PubMedDate not supplied

Low serum hyaluronan in psoriatic arthritis patients in comparison to rheumatoid arthritis patients.

OBJECTIVE: Serum hyaluronan (HA) was determined in 37 patients suffering from psoriatic arthritis (PSA), 39 patients with rheumatoid arthritis (RA), 31 with osteoarthritic joint disease (OA) and 26 healthy controls (C) in order to examine earlier reports that HA levels are increased in the serum of RA and to assess whether this finding is also relevant for PSA, another inflammatory joint disease, since HA in serum is considered a sign of inflammation in general. METHOD: HA in the serum samples was measured with an enzyme linked microplate assay. RESULTS: Sera from PSA, RA and OA patients showed a significantly higher HA concentration than those of healthy controls (56.0 +/- 16.0 micrograms/l). The serum HA concentration in PSA patients amounted to 107.8 +/- 57.2 micrograms/l, which was not significantly different from OA patients (104.9 +/- 16 micrograms/l). A significant difference, however, could be observed between the HA concentrations of the PSA subgroups: the mean HA level of patients suffering from symmetrical polyarthritis was 134 +/- 79.6 micrograms/l, which turned out to be significantly higher than in patients suffering from symmetrical oligoarthritis (89.9 +/- 42.8 micrograms/l; P < 0.04), but was insignificantly increased in comparison to patients with ankylosing spondylitis as the predominant feature (109 +/- 27.8 micrograms/l; P = 0.49). The mean HA concentration for RA sera was 197.1 +/- 122.9 micrograms/l, which was statistically significantly increased compared to PSA (P < 0.001) and OA (P < 0.001) sera. The sera of seropositive RA patients showed significantly higher HA levels than PSA patients with symmetrical polyarthritis (P < 0.04). CONCLUSION: The data obtained support recent studies which have shown HA levels to be higher in RA patients than in OA patients. Seronegative and seropositive RA patients showed the same HA concentrations, while patients suffering from "seronegative" PSA were found to have lower HA concentrations. Therefore, HA serum levels may reflect cartilage degradation in general or the degree of articular inflammatory processes, indicating different pathogenetic pathways.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

Phospholipase A2 activating protein induces tumor regression.

There has been increasing interest in attempts to harness the body's normal inflammatory response mediated through the eicosanoid pathway to treat tumors. Accumulating data indicate that the growth of several different cancers is modulated by a group of pro-inflammatory bioactive lipids, the best known of which are the eicosanoids. Eicosanoid pathway constituents modulate cell function in several important ways, and an agent that activates PLA(2) and up-regulates LTB(4) levels could be expected to be an effective cytotoxic tumor agent, especially if it stimulated NK cells. PLAP is a 28-kDa polypeptide that is a member of the WD-repeat protein, G-protein-transducin superfamily. The pro-inflammatory properties of PLAP have been elucidated using a number of different approaches. PLAP has been found in inflamed tissues and synovial fluid from patients with rheumatoid arthritis. Based on knowledge of PLAP as a pro-inflammatory agent, its capacity to modulate the immune response and the role of the inflammatory and immune responses in immune surveillance, the role of PLAP in cancer therapy was explored. Significant tumor regression was observed 72 hours following a single treatment with PLAP in an animal air pouch model of glioma. PEG-PLAP treatment increased the life expectancy of animals with Lewis lung cancer, and in preliminary studies in MTVL breast tumors in mice, PLAP treatment resulted in a similar increase in life expectancy. These findings suggest that PLAP holds promise as a potential therapy for cancer, and warrants further study.

Journal Article↗