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At least 793 records · Page 44Linked to original sources
PubMed2006

Exercise and psychobiological processes: implications for the primary prevention of coronary heart disease.

Interventions that reduce the magnitude of psychobiological responses are justified, at least in part, by the notion that exaggerated responses to stress can have detrimental effects on health. The biological processes underlying the association between stress and coronary heart disease (CHD) are thought to involve haemodynamic, neuroendocrine, inflammatory and haemostatic pathways. One of the many recognised benefits of exercise is in buffering physiological responses to psychosocial stressors, which is thought to be partly mediated by sympatho-inhibitory mechanisms, although other potentially important psychobiological processes such as inflammatory, neuroendocrine and haemostatic pathways have gained little attention. Thus, the present review focuses on the role of exercise in buffering psychobiological processes, particularly in relation to pathways that are directly relevant for reducing CHD risk. There are inconsistencies in the literature regarding the effects of exercise on cardiovascular responses to stressors, which may in part be accounted for by differences in experimental design, characteristics of participants, inadequate assessment of physical fitness, and the confounding effects of acute exercise. However, new emerging evidence suggests that exercise promotes an anti-inflammatory environment and increases tissue sensitivity to glucocorticoids, which may have implications for the effects of exercise on stress-induced inflammatory pathways. Future work should focus on the efficacy of exercise for promoting anti-inflammatory pathways in relation to psychosocial stress.

Coronary Disease↗
PubMed2005

The role of fatty acid binding proteins in metabolic syndrome and atherosclerosis.

PURPOSE OF REVIEW: The global prevalence of obesity is increasing epidemically. Obesity causes an array of health problems, reduces life expectancy, and costs over US dollar 100 billion annually. More than a quarter of the population suffers from an aggregation of co-morbidities, including obesity, atherosclerosis, insulin resistance, dyslipidemias, coagulopathies, hypertension, and a pro-inflammatory state known as the metabolic syndrome. Patients with metabolic syndrome have high risk of atherosclerosis as well as type 2 diabetes and other health problems. Like obesity, atherosclerosis has very limited therapeutic options. RECENT FINDINGS: Fatty acid binding proteins integrate metabolic and immune responses and link the inflammatory and lipid-mediated pathways that are critical in the metabolic syndrome. This review will highlight recent studies on fatty acid binding protein-deficient models and several fatty acid binding protein-mediated pathways specifically modified in macrophages, cells that are paramount to the initiation and persistence of cardiovascular lesions. SUMMARY: Adipocyte/macrophage fatty acid binding proteins, aP2 and mal1, act at the interface of metabolic and inflammatory pathways. These fatty acid binding proteins are involved in the formation of atherosclerosis predominantly through the direct modification of macrophage cholesterol trafficking and inflammatory responses. In addition to atherosclerosis, these fatty acid binding proteins also exert a dramatic impact on obesity, insulin resistance, type 2 diabetes and fatty liver disease. The creation of pharmacological agents to modify fatty acid binding protein function will provide tissue or cell-type-specific control of these lipid signaling pathways, inflammatory responses, atherosclerosis, and the other components of the metabolic syndrome, therefore offering a new class of multi-indication therapeutic agents.

Animals↗
PubMed2003

Mitogen activated protein (MAP) kinase signal transduction pathways and novel anti-inflammatory targets.

Over the last decade important advances have been made in our understanding of the molecular events underlying cellular responses to extracellular signals. Increased understanding of signal transduction mechanisms and gene regulation involved in immune responses has created opportunities for the discovery of novel therapeutic compounds useful in treating inflammatory disorders. One of the best studied signalling routes is the mitogen activated protein (MAP) kinase signal transduction pathway which plays a crucial role in many aspects of immune mediated inflammatory responses. Here, our current understanding of the MAP kinase pathway is reviewed, as well as recent advances in the design of novel agents that are able to modulate the activity of these signalling cascades.

Eukaryotic Cells↗
PubMed2005

Nitric oxide regulates prolidase activity by serine/threonine phosphorylation.

Prolidase [E.C. 3.4.13.9], a member of the matrix metalloproteinase (MMP) family, is a manganese-dependent cytosolic exopeptidase that cleaves imidodipeptides containing C-terminal proline or hydroxyproline. It plays an important role in collagen metabolism, matrix remodeling and cell growth. Nitric oxide (NO), a versatile signaling molecule, regulates many processes including collagen synthesis and matrix remodeling and, thereby, may modulate angiogenesis, tumor invasiveness, and metastasis. Thus, we considered that prolidase may be an important target of NO regulation. In our study, SIN I and DETA/NO were used as NO donors. Both donors increased prolidase activity in a time-dependent and dose-dependent manner. Prolidase activity increased not only with NO donors but also with endogenous NO in cells transfected with iNOS. The effect of iNOS was abolished by treatment with S-methylisothiourea (SMT), a selective inhibitor of iNOS. However, with either exogenous or endogenous sources of NO, the increase in prolidase activity was not accompanied by increased prolidase expression. Therefore, we suspected phosphorylation of prolidase as a potential mechanism regulating enzyme activation. We observed increased serine/threonine phosphorylation on prolidase protein in cells treated with NO donors and in cells transfected with iNOS. To determinate the pathways that may mediate prolidase induction by NO, we first used 8-Br-cGMP, a cGMP agonist, and found that 8-Br-cGMP strongly and rapidly stimulated prolidase activity accompanied by increased phosphorylation. Rp-8-Br-pCPT-cGMP, an inhibitor of cGMP, reduced NO donor-stimulated prolidase activity to control levels. To test whether the MAPK pathway is involved in this NO-dependent activation, we used an ERK1/2 inhibitor and found that it had no effect on prolidase activity increased by NO donors. These results demonstrate that NO stimulates prolidase activity by increasing serine/threonine phosphorylation through PKG-cGMP pathway, but independent of MAPK and suggest an interaction between inflammatory signaling pathways and regulation of the terminal step of matrix degradation.

Animals↗
PubMed1991

Effects of dietary fish oil on leukocyte leukotriene and PAF generation and on neutrophil chemotaxis.

The studies of dietary fish oil supplementation in healthy volunteers demonstrate: (1) suppression of PMN LTB4 synthesis after a minimum of 4 weeks of dietary fish oil consumption at a level of 4-6 g omega 3 fatty acids daily; concomitant suppression of the other arachidonate-derived 5-lipoxygenase pathway products and decreased [3H]-arachidonic acid release may be observed under certain conditions, (2) suppression of PMN chemotactic responsiveness to LTB4 and FMLP, (3) delayed kinetics of inhibition of chemotaxis and AA metabolism relative to that of cellular lipid alteration, and (4) dietary EPA is more active than DHA in eliciting these effects. The effects of dietary EPA on monocyte function in healthy volunteers include: (1) suppression of LTB4 synthesis concomitantly with that of the other 5-lipoxygenase pathway products and decreased [3H]-arachidonic acid release, (2) suppression of PAF synthesis, and (3) delayed kinetics of inhibition of PAF generation and AA metabolism relative to that of cellular lipid alteration. The effects of dietary fish oil in RA patients include: (1) decreased arachidonate content of cellular lipids with an augmented EPA content, (2) decreased LTB4 generation by PMN as an isolated effect, indicating inhibition of the epoxide hydrolase enzyme. The decrease in LTB4 generation by PMN correlated with improvement of tender joint count in one study, (3) augmentation of depressed PMN chemotaxis to LTB4 and FMLP, and (4) suppression of monocyte PAF generation. From these studies one may conclude that: (1) omega 3 fatty acids are incorporated into leukocyte cellular phospholipids with a concomitant loss in arachidonic acid, (2) the incorporation of omega 3 fatty acids into leukocyte cellular lipids suppresses two pathways of inflammatory mediator synthesis: the 5-lipoxygenase and the PAF synthesis pathways, (3) receptor-mediated PMN functions are altered by dietary omega 3 fatty acid consumption, and (4) these functional changes may be delayed vis-a-vis changes in cellular lipid composition and may vary with the underlying disease states and/or background medication.

Chemotaxis, Leukocyte↗
PubMed2006

Diabetic pregnancies: the challenge of developing in a pro-inflammatory environment.

The maternal diabetic environment alters the embryo and the feto-placental development. The results of these alterations are: increased embryo resorption and malformation rates, placental dysfunction, fetal alterations that lead to increased neonatal morbidity and mortality rates, and also diseases that will be evident later in the adult life of the newborn. The etiology of these many maternal diabetes-induced complications are not yet understood in full. In this review the role of maternal diabetes as an inductor of a pro-inflammatory environment that impairs embryo and placental development is discussed. An overproduction of pro-inflammatory agents is found in the uterus during implantation and the developing embryo and placenta from experimental models of diabetes, as well as in placenta from diabetic women. In these tissues there are increases in reactive oxygen species, pro-inflammatory cytokines and prostaglandins, nitric oxide and peroxynitrites. These pro-inflammatory agents lead to the intrauterine activation of matrix metalloproteinases, proteases involved in remodeling the extracellular matrix during implantation and feto-placental development. Many of these pro-inflammatory agents have overlapping mechanisms of action and cross regulatory pathways that propagate the inflammatory processes. Antioxidants, PPARgamma activators, and NF-kappaB inhibitors are able to reduce the concentrations of these agents in intrauterine gestational tissues. This article reviews the current understanding of maternal diabetes-induced changes in pro-inflammatory and anti-inflammatory pathways that affect the embryo and placental development in maternal diabetes, and stresses the need of a strict maternal control of the pathology to prevent deleterious consequences in the offspring.

Embryo Implantation↗
PubMed2005

Involvement of TLR4/type I IL-1 receptor signaling in the induction of inflammatory mediators and cell death induced by ethanol in cultured astrocytes.

Activated astroglial cells are implicated in neuropathogenesis of many infectious and inflammatory diseases of the brain. A number of inflammatory mediators and cytokines have been proposed to play a key role in glial cell-related brain damage. Cytokine production seems to be initiated by signaling through TLR4/type I IL-1R (IL-1RI) in response to their ligands, LPS and IL-1beta, playing vital roles in innate host defense against infections, inflammation, injury, and stress. We have shown that glial cells are stimulated by ethanol, up-regulating cytokines and inflammatory mediators associated with TLR4 and IL-1RI signaling pathways in brain, suggesting that ethanol may contribute to brain damage via inflammation. We explore the possibility that ethanol, in the absence of LPS or IL-1beta, triggers signaling pathways and inflammatory mediators through TLR4 and/or IL-1RI activation in astrocytes. We show in this study that ethanol, at physiologically relevant concentrations, is capable of inducing rapid phosphorylation within 10 min of IL-1R-associated kinase, ERK1/2, stress-activated protein kinase/JNK, and p38 MAPK in astrocytes. Then an activation of NF-kappaB and AP-1 occurs after 30 min of ethanol treatment along with an up-regulation of inducible NO synthase and cyclooxygenase-2 expression. Finally, we note an increase in cell death after 3 h of treatment. Furthermore, by using either anti-TLR4- or anti-IL-1RI-neutralizing Abs, before and during ethanol treatment, we inhibit ethanol-induced signaling events, including NF-kappaB and AP-1 activation, inducible NO synthase, and cyclooxygenase-2 up-regulation and astrocyte death. In summary, these findings indicate that both TLR4 and IL-1RI activation occur upon ethanol treatment, and suggest that signaling through these receptors mediates ethanol-induced inflammatory events in astrocytes and brain.

Animals↗
PubMed2004

Chronic ethanol treatment enhances inflammatory mediators and cell death in the brain and in astrocytes.

Inflammatory processes and cytokine expression have been implicated in the pathogenesis of several neurodegenerative disorders. Chronic ethanol intake induces brain damage, although the mechanisms involved in this effect are not well understood. We tested the hypothesis that activation of glial cells by ethanol would induce stimulation of signaling pathways and inflammatory mediators in brain, and would cause neurotoxicity. We used cerebral cortex from control and chronic ethanol-fed rats, which received ethanol-liquid diet for 5 months and cultured of astrocytes exposed to 75 mM ethanol for 7 days. Our results demonstrate that chronic ethanol treatment up-regulates iNOS, COX-2 and IL-1beta in rat cerebral cortex and in cultured astrocytes. Under both experimental conditions, up-regulation of these inflammatory mediators and IL-1RI concomitantly occurs with the stimulation of IRAK and MAP kinases, including ERK1/2, p-38 and JNK, which trigger the downstream activation of oxidant-sensitive transcription factors NF-KB and AP-1. These effects were associated with an increased in both caspase-3 and apoptosis in ethanol-fed rats and in astrocytes exposed to ethanol. In conclusion, chronic ethanol treatment stimulates glial cells, up-regulating the production and the expression of inflammatory mediators in the brain, and activating signalling pathways and transcription factors involved in inflammatory damage and cell death.

Animals↗
PubMed2004

Inhibition of inducible nitric-oxide synthase by activators of AMP-activated protein kinase: a new mechanism of action of insulin-sensitizing drugs.

AMP-activated protein kinase (AMPK), an energy-sensing enzyme that is activated in response to cellular stress, is a critical signaling molecule for the regulation of multiple metabolic processes. AMPK has recently emerged as an attractive novel target for the treatment of obesity and type 2 diabetes because its activation increases fatty acid oxidation and improves glucose homeostasis. Here we show that pharmacological activation of AMPK by insulin-sensitizing drugs markedly inhibits inducible nitric-oxide synthase (iNOS), a proinflammatory mediator in endotoxic shock and in chronic inflammatory states including obesity-linked diabetes. AMPK-mediated iNOS inhibition was observed in several cell types (myocytes, adipocytes, macrophages) and primarily resulted from post-transcriptional regulation of the iNOS protein. AMPK activation in vivo also blunted iNOS induction in muscle and adipose tissues of endotoxin-challenged rats. Reduction of AMPK expression by small interfering RNA reversed the inhibitory effects of AMPK activators on iNOS expression and nitric oxide production in myocytes. These results indicate that AMPK is a novel anti-inflammatory signaling pathway and thus represents a promising therapeutic target for immune-inflammatory disorders.

3T3 Cells↗
PubMed2006

Nitric oxide and reactive nitrogen species in airway epithelial signaling and inflammation.

Nitric oxide (NO(.-)) is produced by many diverse cell types as a cellular or intracellular signaling molecule, by the activation of nitric oxide synthases (NOSs). All three known NOS isoforms are expressed within the respiratory tract and mediate various airway functional properties such as airway smooth muscle tone, ciliary function, epithelial electrolyte transport, and innate host defense. The respiratory epithelium is a major source of NO(.-), in which it regulates normal epithelial cell function and signaling as well as signaling pathways involved in airway inflammation. In addition to its normal physiological properties, increased airway NO(.-) production in inflammatory respiratory tract diseases such as asthma may activate additional signaling mechanisms to regulate inflammatory-immune pathways, and epithelial barrier (dys)function or repair. The biological actions of NO(.-) are controlled at various levels, including mechanisms that regulate NOS localization and activation, and variable oxidative metabolism of NO(.-), resulting in generation of bioactive reactive nitrogen species (RNS). Moreover, in addition to altered production of NO(.-) or RNS, the presence of various target enzymes and/or metabolic regulators of NO(.-)/RNS can be dramatically altered during airway inflammatory conditions, and contribute to alterations in NO(.-)-mediated signaling pathways in disease. This review summarizes current knowledge regarding NO(.-)-mediated epithelial signaling, as well as disease-related changes in airway NOS biology and target enzymes that affect NO(.-)/RNS signaling mechanisms. A detailed understanding of these various changes and their impact on NO(.-) signaling pathways are needed to fully appreciate the contributions of NO(.-)/RNS to airway inflammation and to develop suitable therapeutic approaches based on regulating NO(.-) function.

Animals↗
PubMed2005

Interaction between a rat model of cerebral ischemia and beta-amyloid toxicity: II. Effects of triflusal.

BACKGROUND AND PURPOSE: Clinical data suggest that Alzheimer disease (AD) and stroke together potentiate cognitive impairment. Our rat model demonstrates that this interaction may be mediated through inflammatory cells and pathways. Thus, anti-inflammatory agents such as Triflusal, a nonsteroidal anti-inflammatory agent (NSAID), may provide neuroprotection for susceptible neurons in AD and cerebral ischemia. METHODS: AD was modeled by cerebroventricular injections of beta-amyloid (Abeta25-35) and subcortical lacunar infarcts by striatal endothelin injections. Inflammatory mechanisms were examined by immunohistochemical analysis. Behavioral tasks were assessed with the Montoya staircase test. RESULTS: Triflusal reduced pathologic and inflammatory markers and functional deficits in rats receiving Abeta or endothelin alone but was less effective in the more severe pathology of the combined Abeta/endothelin model. CONCLUSIONS: Higher doses or more prolonged treatment with NSAIDs may be required for more effective neuroprotection in combined AD and stroke conditions.

Alzheimer Disease↗
PubMed2004

Curcumin inhibits NF-kappaB activation and reduces the severity of experimental steatohepatitis in mice.

BACKGROUND/AIMS: While oxidative stress is a feature of non-alcoholic steatohepatitis, the causal link between oxidative stress and inflammatory recruitment has yet to be demonstrated. We analysed the role of NF-kappaB redox-sensitive signalling pathway of inflammatory recruitment in experimental steatohepatitis. METHODS: Mice were fed the methionine and choline deficient (MCD) or the control diet, with or without curcumin, an NF-kappaB inhibitor, for up to 4 weeks. Histopathology, lipoperoxides, NF-kappaB/DNA binding and expression of NF-kappaB-regulated genes were assessed. RESULTS: MCD-fed mice developed steatohepatitis accompanied by dramatic accumulation of hepatic lipoperoxides, activation of NF-kappaB and induction of pro-inflammatory ICAM-1, COX-2, MCP-1 and CINC mRNA. Curcumin significantly reduced MCD-induced inflammation but had no effect on steatosis or on the level of hepatic lipid peroxides. Curcumin prevented the MCD-induced activation of NF-kappaB and decreased downstream induction of ICAM-1, COX-2 and MCP-1. However, it failed to reduce activation of AP-1, MAPK pathways or CINC expression. CONCLUSIONS: Curcumin alleviates the severity of hepatic inflammation in experimental steatohepatitis induced by the MCD diet, an effect likely to be mediated via inhibition of NF-kB activation and dependent pro-inflammatory genes. The NF-kappaB pathway is one among several possible signalling pathways by which inflammation is recruited in experimental steatohepatitis.

Animals↗
PubMed2006

Differential involvement of NF-kappaB and MAP kinase pathways in the generation of inflammatory cytokines by human neutrophils.

The ability of human neutrophils to express a variety of genes encoding inflammatory mediators is well documented, and mounting evidence suggests that neutrophil-derived cytokines and chemokines contribute to the recruitment of discrete leukocyte populations at inflammatory sites. Despite this, our understanding of the signaling intermediates governing the generation of inflammatory cytokines by neutrophils remains fragmentary. Here, we report that inhibitors of the p38 MAPK and MEK pathways substantially diminish the release of (and in the case of p38 inhibitors, the gene expression of) several inflammatory cytokines in neutrophils stimulated with LPS or TNF. In addition, various NF-kappaB inhibitors were found to profoundly impede the inducible gene expression and release of inflammatory cytokines in these cells. The MAPK inhibitors did not affect NF-kappaB activation; instead, the transcriptional effects of the p38 MAPK inhibitor appear to involve transcriptional factor IID. Conversely, the NF-kappaB inhibitors failed to affect the activation of MAPKs. Finally, the MAPK inhibitors were found to prevent the activation a key component of the translational machinery, S6 ribosomal protein, in keeping with their post-transcriptional impact on cytokine generation. To our knowledge, this constitutes the first demonstration that in neutrophils, the inducible expression of proinflammatory cytokines by physiological stimuli largely reflects the ability of the latter to activate NF-kappaB and selected MAPK pathways. Our data also raise the possibility that NF-kappaB or MAPK inhibitors could be useful in the treatment of inflammatory disorders in which neutrophils predominate.

Boronic Acids↗
PubMed2005

Effect of nuclear factor-kappaB inhibition on rheumatoid fibroblast-like synoviocytes and collagen induced arthritis.

OBJECTIVE: The nuclear factor-kB (NF-kB) signaling pathway has been implicated as a molecular target for the treatment of various inflammatory diseases, such as rheumatoid arthritis (RA). In particular, IkB kinase (IKK) is considered an important molecular target because the majority of inflammatory signaling pathways mediated by NF-kB involve IKK activation. We investigated the effect of NF-kB inhibition on rheumatoid fibroblast-like synoviocytes (FLS) and collagen induced arthritis. METHODS: We evaluated the effect of IMD-0560, an inhibitor of IKK, on rheumatoid FLS in vitro and on collagen type II induced arthritis in mice. RESULTS: IMD-0560 suppressed the nuclear translocation of NF-kB and phosphorylation of IkBa induced by tumor necrosis factor-a in FLS. In addition, this compound suppressed the production of inflammatory cytokines, including interleukin 6 (IL-6), IL-8, and monocyte chemoattractant protein-1. IMD-0560 also inhibited the proliferation of FLS without showing cellular toxicity. Finally, this compound was effective against collagen induced arthritis in mice. CONCLUSION: Based on these results, IMD-0560 could be a new therapeutic agent for RA.

Animals↗
PubMed2005

Mycobacterium tuberculosis heat shock proteins use diverse Toll-like receptor pathways to activate pro-inflammatory signals.

Although the Toll-like receptors used by Mycobacterium tuberculosis membrane and secreted factors are known, the pathways activated by M. tuberculosis heat shock proteins are not. An efficient immune response against the intracellular pathogen M. tuberculosis is critically dependent on rapid detection of the invading pathogen by the innate immune system and coordinated activation of the adaptive immune response. Macrophage phagocytosis of M. tuberculosis is accompanied by activation of the transcription factor NF-kappaB and secretion of inflammatory mediators that play an important role in granuloma formation and immune protection during M. tuberculosis infection. The interaction between M. tuberculosis and the various Toll-like receptors is complex, and it appears that distinct mycobacterial components may interact with different members of the Toll-like receptor family. Here we show that recombinant, purified, mycobacterial heat shock proteins 65 and 70 induce NF-kappaB activity in a dose-dependent manner in human endothelial cells. Furthermore, we show that whereas mycobacterial heat shock protein 65 signals exclusively through Toll-like receptor 4, heat shock protein 70 also signals through Toll-like receptor 2. Mycobacterial heat shock protein 65-induced NF-kappaB activation was MyD88-, TIRAP-, TRIF-, and TRAM-dependent and required the presence of MD-2. A better understanding of the recognition of mycobacterial heat shock proteins and their role in the host immune response to the pathogen may open the way to a better understanding of the immunological processes induced by this important human pathogen and the host-pathogen interactions and may help in the rational design of more effective vaccines or vaccine adjuvants.

Animals↗
PubMed2025

Elucidation of the immunotoxicity of PEDOT: PSS on RAW264.7 macrophages by oxidative stress, inflammatory response, and NF-κB pathway activation.

Poly(3,4-ethylenedioxythiophene): poly(styrenesulfonate) (PEDOT: PSS) nanoparticles, widely used conductive polymers, pose environmental and health risks due to their nanoscale dispersion. However, the characteristics of PEDOT: PSS in aquatic systems and the underlying mechanisms of its toxicity in animal and cell models remain poorly understood. This study aimed to investigate the toxicological effects of PEDOT: PSS nanoparticles on macrophages, with a focus on RAW 264.7 cells. After an acute exposure to PEDOT: PSS nanoparticles at different concentrations (5, 10, 20 μg/mL), we observed significant impairments in cell viability, proliferation, migration, adhesion, and phagocytosis, as well as morphological alterations. Concurrently, there was a marked upregulation of inflammatory markers, including reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β), indicating the induction of oxidative stress and inflammation. Mechanistically, PEDOT: PSS nanoparticles activated the nuclear factor kappa B (NF-κB) signaling pathway, a key regulator of inflammatory responses, suggesting that they may mediate inflammatory responses and cell damage via activation of the NF-κB signaling pathway. These findings reveal the toxic mechanism of PEDOT: PSS nanoparticles in macrophages and provide new insights into their biological safety implications.

Animals↗
PubMed2001

Specificity, diversity, and convergence in VEGF and TNF-alpha signaling events leading to tissue factor up-regulation via EGR-1 in endothelial cells.

Tissue factor (TF) has been shown to be up-regulated in endothelial cells by the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) as well as by the main angiogenic factor VEGF. Since both stimuli induce the transcription factor EGR-1, which is critically involved in TF gene regulation, we used EGR-1-dependent TF induction as a model to identify potential cross-talks between the various signal transduction cascades initiated by VEGF and TNF-alpha. The data show that at the MAP kinase level, VEGF mainly activates ERK1/2 and p38 MAP kinases in human endothelial cells. TNF-alpha is able to activate all three MAP kinase cascades as well as the classical inflammatory IkappaB/NFkappaB pathway. Furthermore, the MEK/ERK module of MAP kinases appears to act as the convergence point of VEGF- and TNF-alpha-initiated signaling cascades, which lead to the activation of EGR-1 and subsequent TF expression, whereas the upstream signals are distinct. We found that induction of TF by VEGF via EGR-1 is strongly PKC dependent. The TNF-alpha-initiated MEK/ERK cascade connected to EGR-1 and TF expression is clearly less sensitive to PKC inhibition. TNF-alpha-mediated activation of MEK/ERK and EGR-1 can be blocked by adenoviral expression of a dominant negative mutant of IKK2, whereas the VEGF signaling pathway is unaffected. Thus, our data demonstrate a new link between the classical inflammatory IKK/IkappaB and the MEK/ERK cascades triggered by TNF-alpha. The additional finding that EGF induces ERK and EGR-1 in a PKC-independent manner and that this signal is not sufficient to up-regulate TF emphasizes the importance of a VEGF-specific signaling pattern for the induction of TF.

Cells, Cultured↗
PubMed1996

The stress activated protein kinase pathway.

The SAPKs represent novel conduits through which the effects of cellular insults or injury are transmitted to the nucleus to influence gene expression. The SAPK pathway consists of at least four levels of protein kinases that are activated by a wide range of agents that adversely affect cell growth. Unlike the structurally related MAPK pathway, the stress induced kinases are not required for mitogenesis and instead induce growth arrest. Given the modulation of the pathway by inflammatory cytokines, reperfusion injury and chemotherapeutics, determination of the physiological functions of the pathway may uncover new possibilities for diagnosis and therapeutic intervention.

Animals↗